High enantioselectivity is induced by a single monodentate phosphoramidite ligand in iridium-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1002/anie.200603930

(Chemical Equation Presented) The Full Monty? Stripping a catalyst down to its bare essentials gives a neutral iridium complex containing only one monodentate phosphoramidite ligand that is an efficient catalyst for the enantioselective hydrogenation of α-dehydroamino acids (see picture).

Full text of DOI:10.1002/anie.200603930

Angewandte
Chemie
DOI: 10.1002/anie.200603930
Asymmetric Hydrogenation
High Enantioselectivity Is Induced by a Single Monodentate
Phosphoramidite Ligand in Iridium-Catalyzed Asymmetric
Hydrogenation**
Francesca Giacomina, Auke Meetsma, Lavinia Panella, Laurent Lefort,* AndrØ H. M. de Vries,
and Johannes G. de Vries*
Bidentate chiral ligands were the rule in metal-catalyzed
asymmetric hydrogenation for more than 30 years[1] as
chelation was believed to be necessary to impart the necessary
rigidity to the metal complex for an efficient transfer of
chirality. Recently, however, a few groups have demonstrated
that monodentate ligands can also induce high enantioselec-
tivity[2] as long as two of these ligands are present in the active
species. Herein, we describe the first example of a highly
asymmetric hydrogenation that is induced by a metal catalyst
containing only one monodentate ligand.[3]
Iridium is an important metal in hydrogenation. The
Crabtree catalyst,[4] its enantioselective version, developed by
Pfaltz, based on chiral P,N ligands,[5] or the celebrated
Metolachlor process catalyst[6] are prime examples of Ir-
based hydrogenation catalysts (Scheme 1). We were inter-
Scheme 1. Iridium catalysts.
ested in investigating whether iridium complexes of chiral
monodentate phosphoramidites could also act as efficient
enantioselective hydrogenation catalysts. Although such Ir
complexes have already been reported,[7] which has led to the
discovery of new cyclometalated species that are active in
allylic substitution,[8] there are no reports of their use in
enantioselective hydrogenation.
Our initial studies were aimed at the preparation of
cationic iridium complexes that are analogues of the Crabtree
catalyst containing a phosphoramidite ligand L, and either the
same phosphoramidite, a phosphine, or pyridine as the
secondary ligand L’ (Scheme 1). Based on literature prece-
dents,[9] two equivalents of Monophos were treated with
[{Ir(cod)Cl}2] to immediately give [Ir(cod)(L)Cl][7b] which,
upon chloride abstraction in the presence of another equiv-
alent of L, should form a cationic complex of the type
[Ir(cod)LL’]+. Although we screened several phosphorami-
dites in combination with different ancillary ligands and
counteranions, we did not obtain an efficient hydrogenation
catalyst. The breakthrough came with the observation that an
active but also enantioselective catalyst is obtained with bulky
phosphoramidites based on Binol with substituents in the 3,3’
positions without abstraction of the chloride ligand, that is,
from the non-cationic catalyst precursor [Ir(cod)(L)Cl] con-
taining only one phosphoramidite ligand per metal.[10]
The drastic effect of the substitution in the 3,3’ positions of
the diol backbone of the ligand can be visualized by
comparing the hydrogen uptake curves obtained during the
hydrogenation
of
methyl
(Z)-2-acetamidocinnamate
(Figure 1). Figure 1 clearly shows that increasing the bulki-
ness of the chiral backbone in the 3,3’ positions leads to a
substantial increase not only in activity but also in enantio-
selectivity (average TOFs of 6, 24, 50, and 150 hÀ1 and ee
values of 28, 67, 93, and 98% for R1 = H, Me, Ph, and R2 =
tBu, respectively; see also Scheme 1). For practical reasons,
namely that the diol precursor is commercially available, the
bulkiest ligand with the tBu substituents is based on biphenol
while the other ligands are based on binaphthol.[12] Increasing
the bulkiness of the phosphoramidite by changing its amino
moiety does not, however, produce the same effect, and the
catalytic performance of the complex remained poor when
the dimethylamino group was substituted by a bis(a-methyl-
benzyl)amino group with unsubstituted binaphthol as back-
bone. This indirectly reinforces our assumption about the
major role played by substitution in the 3,3’ positions of the
[*] F. Giacomina,Dr. L. Panella,Dr. L. Lefort,Dr. A. H. M. de Vries,
Prof. Dr. J. G. de Vries
DSM Pharmaceutical Products—Advanced Synthesis,Catalysis &
Development
P.O. Box 18,6160 MD Geleen (The Netherlands)
Fax: (+31)46-476-7604
E-mail: laurent.lefort@dsm.com
hans-jg.vries-de@dsm.com
A. Meetsma
Crystal Structure Center
Materials Science Center
University of Groningen
Nijenborgh 4,9747 AG Groningen (The Netherlands)
[**] We thank Jeroen A. F. Boogers for assistance and helpful discus-
sions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Figure 1. Hydrogen consumption during the hydrogenation of methyl
(Z)-2-acetamidocinnamate with various Ir/phosphoramidite catalysts
(Ir/L/substrate=0.01/0.01/0.5 mmol).[11]
Figure 2. ORTEP representation of the structure of [Ir(cod)(L4)Cl];
selected bond lengths [Š] with estimated standard deviations: Ir-Cl
2.362(2),Ir-P 2.265(3),Ir-C1 2.126(9),Ir-C4 2.224(10),Ir-C5 2.232(10),
Ir-C8 2.143(9),C1-C8 1.435(16),C4-C5 1.397(17).
ligand diol backbone. A similar effect has also been reported
by Ojima for rhodium-catalyzed hydroformylation reac-
tions.[12]
In order to confirm that the catalyst precursor contains
only one phosphoramidite ligand per metal ion, we undertook
a full characterization of the complex by NMRspectroscopy,
X-ray diffraction, and elemental analysis. The addition of two
equivalents of L4 to [Ir(cod)Cl]2 (Ir/L = 1/1) led to the
complete disappearance of the 31P NMRsignal of the free
ligand L4 at d = 141.1 ppm and the appearance of a single
peak at d = 107.8 ppm (bound L4). If more L4 is added, no
change is observed except for the appearance of the free-
ligand peak. The behavior of L1 is different. Thus, if more than
two equivalents of L1 per [Ir(cod)Cl]2 is used, a new Ir
complex exhibiting two sets of doublet (d = 94.5 and
88.6 ppm, J = 38.6 Hz) is observed in addition to a singlet at
d = 117.6 ppm for [Ir(cod)(L1)Cl]. This pattern is consistent
with an iridium complex containing two nonequivalent L1
moieties.
Crystals of the complex formed upon reaction of [Ir-
(cod)Cl]2 with L4 were obtained from a dichloromethane/
heptane solution and studied by X-ray diffraction. The crystal
structure of this complex is presented in Figure 2.[13]
Although the catalyst precursor was fully characterized as
a complex containing a single phosphoramidite ligand, the
ligand-to-iridium ratio may be more than one in the active
species responsible for the hydrogenation. However, several
facts seem to prove that this is not the case:
1. Bulky ligands are necessary for activity and enantioselec-
tivity: As we have seen previously, the less bulky L1, which
is more suitable for formation of an [Ir(L1)2]+ complex,
does not lead to an active catalyst although it is electroni-
cally equivalent to L4. This seems to demonstrate that a
bulky ligand is necessary to stabilize an [IrL] species. It
might also help to prevent dimerization, which is a
common cause of deactivation of iridium hydrogenation
catalysts.[4b]
2. No acceleration is observed in the presence of additional
ligand: If one additional equivalent of ligand L4 is added to
isolated [Ir(cod)(Cl)L4] prior to the hydrogenation, the
hydrogenation reaction proceeds slightly slower. The
opposite would be observed if the active species were of
the type [IrLn] (n > 1) as more of this species would be
present in solution.
3. The absence of a nonlinear effect:[14] The ee value of 2
varies linearly with that of the ligand L4.[15] For phosphor-
amidites[16a] and phosphonites,[16b] a positive nonlinear
effect has been observed in the case of Rh, where it is
accepted that the active species contains two ligand
molecules per metal ion.
4. The absence of a ligand mixture effect: One of the
advantages of monodentate ligands in an ML2 complex is
the possibility of using mixtures of ligands La and Lb to
form new catalysts of the type MLaLb.[17] The addition of
one equivalent of (R)-L1 to [Ir(cod)((S)-L4)Cl] prior to the
hydrogenation does not decrease the ee value of 2.
Although this chiral poisoning experiment does not
constitute a definite proof, it shows that the active
hydrogenation species containing L4 does not accommo-
date an extra phosphoramidite ligand L1 to form the cation
[Ir((S)-L4)((R)-L1)]+.
We briefly investigated the scope of the catalyst with
various amino acid precursors (Table 1). The catalyst exhibits
high activity and enantioselectivity with both electron-poor
and electron-rich substituted methyl (Z)-2-acetamidocinna-
mates (Table 1, entries 2 and 3). A high ee value is also
obtained upon hydrogenation of the acid, although the
catalysis becomes rather slow (Table 1, entry 4). With smaller
substrates such as methyl 2-acetamidoacrylate (Table 1,
entry 5), the ee value drops to 50%. A further drop is
observed when the N-acetyl group is replaced by an N-formyl
group (Table 1, entry 6).[18] However, increasing the bulk of
the alkyl residue of the substrate again leads to a high ee value
(Table 1, entry 7). A standard enamide (N-(1-phenylvinyl)-
acetamide) was also tested under the same conditions. It gave
full conversion but only a low ee value (10%). These results
are quite informative. First of all, they show that a single-
ligand catalyst is more efficient with relatively bulky sub-
strates. Such substrates might form a more rigid assembly with
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Table 1: Conversion and ee values obtained with [Ir(cod)(L4)Cl] in the
Endeavor reactor. The Endeavor is an autoclave that contains eight
hydrogenation of various dehydroamino acids.[a]
reactors equipped with glass reaction vessels. Substrate (0.5 mmol),
[{Ir(cod)Cl}2] (0.01 mmol), and ligand (0.02 mmol) were weighed into
these reaction vessels. The vessels were placed in the reactors and
CH2Cl2 (5 mL) was added. The reactors were purged for 30 min with
N2 before applying a hydrogen atmosphere of 5 bar. The pressure was
kept constant during the reaction and the hydrogen uptake was
monitored. After completion of the reaction, the reactors were
opened and samples were taken for ee determination by GC.
Entry
Substrate
Conv. [%] TOF [hÀ1 [b]
]
ee [%]
R
R’
R’’
1[c]
2
3
4
5
Ph
Me
Me
Me
H
Me
Me
Me
Me
Me
Me
Me
Me
H
100
100
100
50
100
89
150
25
25
9
273
30
1
98
98
98
98
50
39
88
p-MeOC6H4
p-ClC6H4
Ph
H
H
Received: September 25, 2006
Published online: January 16, 2007
6
7[d]
iPr
H
89
Keywords: asymmetric catalysis · hydrogenation · iridium ·
.
P ligands · phosphoramidites
[a] Ir/L/substrate=0.01/0.01/0.5 mmol,CH 2Cl2,room temperature,
5 bar H2. [b] Average TOF estimated from H2 consumption curve.
[c] The hydrogenation of this substrate was also performed at 25 bar H2,
which led to an increase in rate but no change in ee. [d] Substrate/
catalyst ratio of 25:1.
[1] a) T. Ohkuma, M. Kitamura, R. Noyori in Catalytic Asymmetric
Synthesis (Ed.: I. Ojima), Wiley-VCH, Weinheim, 2000, p. 1;
b) J. M. Brown in Comprehensive Asymmetric Catalysis, Vol. 1
(Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
Heidelberg, 2004, p. 121; c) The Handbook of Homogeneous
Hydrogenation (Eds.: J. G. de Vries, C. J. Elsevier), Wiley-VCH,
Weinheim, 2007.
the catalyst because of steric congestion, thus allowing an
efficient transfer of chirality. Secondly, although we cannot
rule out h6 coordination in the case of the phenylalanine
precursor[19] as an explanation for the ee value obtained with
this substrate, this is not a prerequisite, as observed in entry 7
of Table 1.
Although the true nature of the active species in
homogeneous catalysis is often difficult to ascertain unam-
biguously, our observations point towards an iridium complex
with a single monodentate ligand as the active species. We
believe this is a unique example of high enantioselectivity
induced by a catalyst that has been pared down to the bare
essentials. It is conceivable, though, that secondary interac-
[2] a) F. Guillen, J. C. Fiaud, Tetrahedron Lett. 1999, 40, 2939; b) M.
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[3] To the best of our knowledge, there are only two earlier reports
of the use of complexes with a chiral monodentate ligand to
metal ratio of 1:1 as catalysts in asymmetric hydrogenation. The
ee values obtained were low to moderate: a) X. Jiang, A. J.
Minnaard, B. Hessen, B. L. Feringa, A. L. L. Duchateau, J. G. O.
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tions between iridium and the monodentate ligand are
[8,21]
induced either due to an h2 interaction[20] or C H insertion
À
upon hydrogenation of cod, which would transform our
monodentate ligand into a bidentate ligand. We are currently
investigating the structure of the catalyst during hydrogena-
tion by NMRspectroscopy and mass spectrometry.
Experimental Section
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General procedures: All reactions were performed under dry nitro-
gen using standard Schlenk techniques or in a glove box. Anhydrous
solvents dried over molecular sieves (Fluka) were used systematically.
[{Ir(cod)Cl}2] and Biphen were purchased from Strem. The hydro-
genation substrates were synthesized following published procedures.
Preparation
of
[Ir(cod)(L4)Cl]:
[{Ir(cod)Cl}2]
(65 mg,
0.096 mmol) was placed in a 10-mL Schlenk flask and the entire
apparatus was evacuated and back-filled with N2 three times to
establish an inert atmosphere. Dry, degassed dichloromethane (1 mL)
and (S)-L4 (82 mg, 0.192 mmol) were added and the reaction mixture
was stirred at room temperature for 10 min. X-ray quality crystals
were obtained upon layering with n-heptane. 1H NMR(300 MHz,
CDCl3): d = 7.22 (s, 1H), 7.09 (s, 1H), 5.40–5.29 (m, 1H), 5.24–5.13
(m, 1H), 3.57–3.47 (m, 1H), 2.83–2.74 (m, 1H), 2.61 (br, 3H), 2.58 (br,
3H), 2.26 (s, 3H), 2.24 (s, 3H), 1.80 (s, 3H), 1.71 (s, 3H), 1.65 (s, 9H),
1.37 ppm (s, 9H); 31P NMR(121.5 MHz, CDCl 3): d = 107.8 ppm;
elemental analysis calcd (%) for C34H50ClIrNO2P: C 53.49, H 6.60, N
1.83; found: C 53.4, H 6.8, N 1.8.
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with monitoring of the H2 consumption were performed in an
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Communications
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[15] See the Supporting Information.
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