Kinetic study of various phosphoramidite ligands in the iridium-catalyzed allylic substitution

Article abstract of DOI:10.1021/ol050350w

(Graph Presented) A comparative kinetic study of seven ligands is presented which clearly shows that a slight difference in the substitution pattern of the aryl group on the amine moiety of the ligand dramatically alters the activity of the resulting iridium catalyst. Ligand L6 shows the most impressive kinetics as well as the highest enantioselectivities.

Full text of DOI:10.1021/ol050350w

ORGANIC
LETTERS
2005
Vol. 7, No. 8
1621-1624
Kinetic Study of Various
Phosphoramidite Ligands in the
Iridium-Catalyzed Allylic Substitution
Damien Polet and Alexandre Alexakis*
Department of Organic Chemistry, UniVersity of GeneVa, 30, quai Ernest Ansermet,
CH-1211 GeneVa 4, Switzerland
alexandre.alexakis@chiorg.unige.ch
Received February 18, 2005
ABSTRACT
A comparative kinetic study of seven ligands is presented which clearly shows that a slight difference in the substitution pattern of the aryl
group on the amine moiety of the ligand dramatically alters the activity of the resulting iridium catalyst. Ligand L6 shows the most impressive
kinetics as well as the highest enantioselectivities.
Asymmetric allylic substitution (eq 1) has been shown to
be a powerful method for the preparation of a wide range of
chiral molecules. This reaction has generated a great deal of
interest in recent years, and several methods have been
developed for the control of both regio- and stereochemistry.
Using [IrCODCl]2 and L1 (Figure 1) as the chiral source,
Hartwig observed an induction period; he isolated and
characterized the postulated catalytically active species
resulting from the insertion of the iridium metal into a C-H
bond of the methyl group of the amine part of L1.5
Very recently, our group described a new phosphoramidite
ligand L2 that contains two o-methoxy substituents on the
(2) (a) Pre´toˆt, R.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 323-325.
(b) Glorius, F.; Neuburger, M.; Pfaltz, A. HelV. Chim. Acta 2001, 84, 3178-
3196. (c) You, S.-L.; Zhu, X.-Z.; Luo, Y.-M.; Hou, X.-L.; Dai, L.-X. J.
Am. Chem. Soc. 2001, 123, 7471-7472. (d) Hou, X.-L.; Sun, N. Org. Lett.
2004, 6, 4399-4401 and references cited herein.
Among the metals that are used for this reaction, palladium
has been the most widely studied.1 The regiochemistry of
this metal normally favors the linear product, although
nowadays there are more and more examples of branched
regioselectivity.2 Among other metals, increasing interest is
devoted to Ir3,4 which gives regioselectivities more generally
in favor of branched products.
(3) For a review on Ir, see: Takeuchi, R. Synlett 2002, 1954-1965.
(4) (a) Takeuchi, R.; Kashio, M. Angew. Chem., Int. Ed. Engl. 1997,
36, 263-265. (b) Bartels, B.; Helmchen, G. Chem. Commun. 1999, 741-
742. (c) Bartels, B.; Helmchen, G.; Garcia-Yebra, C. Eur. J. Org. Chem.
2003, 1097-1103. (d) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002,
124, 15164-15165. (e) Lo´pez, F.; Ohmura, T.; Hartwig, J. F. J. Am. Chem.
Soc. 2003, 125, 3426-3427. (f) Shu, C.; Hartwig John, F. Angew. Chem.,
Int. Ed. 2004, 43, 4794-4797. (g) Shu, C.; Leitner, A.; Hartwig John, F.
Angew. Chem., Int. Ed. 2004, 43, 4797-4800. (h) Lipowsky, G.; Helmchen,
G. Chem. Commun. 2004, 116-117. (i) Welter, C.; Koch, O.; Lipowsky,
G.; Helmchen, G. Chem. Commun. 2004, 896-897. (j) Garcia-Yebra, C.;
Janssen, J. P.; Rominger, F.; Helmchen, G. Organometallics 2004, 23,
5459-5470.
(1) (a) Trost, B. M.; Lee, C. In Catalytic Asymmetric Synthesis, 2nd ed.;
Ojima, I., Ed.; Wiley-VCH: New York, 2000; p 593. (b) Pfaltz, A.; Lautens,
M. In ComprehensiVe Asymmetric Catalysis I-III; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Berlin, 1999; p 833. (c) Guiry, P. J.;
Saunders: C. P. AdV. Synth. Catal. 2004, 346, 497-537.
(5) Kiener, C. A.; Shu, C.; Incarvito, C.; Hartwig, J. F. J. Am. Chem.
Soc. 2003, 125, 14272-14273.
10.1021/ol050350w CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/18/2005

Figure 1. Chiral ligands used in this study.
amine part of the ligand. L2 showed, both in the Ir-catalyzed
allylic amination and alkylation of many allylic carbonates
and acetates, a spectacular acceleration of the reaction6 with
high regio- and enantioselectivities.7 Almost simultaneously,
Helmchen tested L2 in his conditions and also noticed
acceleration as well as an improvement of the enantioselec-
tivity compared to L1.8
At first glance, we logically assumed that the efficiency
of our new ligand was due to the P-O hemilabile character
(Scheme 1), although it would lead to a seven-membered
metallo-ring and kick out a chloride anion.
on the related ligand L410 could sustain such an assumption.
Nevertheless, we have not been able to observe any
1
coordination of the o-methoxy group by H or 31P NMR or
get any crystals suitable for X-ray structure analysis.
To confirm or deny this hypothesis, we focused our
attention in doing specific structural changes in the amine
part of this family of ligands. Using our very efficient
synthetic method leading to secondary amines,11 we prepared
several C2- and pseudo-C2-symmetrical amines to show the
impact of ortho substitution of the aromatic ring in the amino
part of seven different ligands (Table 1). The nonsymmetrical
amines A4 and A5 were prepared for the sake of convenience
because all of the starting materials are commercially
available. The synthesis of amines A2 and A6 requires a
chiral amine that has to be synthesized or obtained generously
from BASF. The calculations on L4 showed that a single
methoxy group had the same impact as two.
Scheme 1. Initial Postulate Concerning the Efficiency of L2
over L1
With the new ligands in hand, we used them in the iridium-
catalyzed allylic amination reaction using benzylamine as
the nucleophile. The results of the kinetics are presented in
Figure 2. Bearing a methoxy substituent in the para position,
ligand L3 was used to give hints concerning an eventual
electronic effect. This did not seem to be the case as the
Indeed, it was legitimate to consider L2 as a bidentate
ligand, allowing a stronger positive character to enhance the
oxidative addition to the substrate.9 Preliminary calculations
Table 1. Synthesis of C2-Symmetrical and Pseudo-C2-symmetrical Secondary Amines
entry
Ar1
Ar2
amine (dr)a
yield of amineb (%)
ligand
yield of ligand (%)
1
2
3
4
5
6
o-MeOC6H4
p-MeOC6H4
Ph
Ph
o-CH3C6H4
1-naphthyl
o-MeOC6H4
p-MeOC6H4
o-MeOC6H4
o-CH3C6H4
o-CH3C6H4
1-naphthyl
A2 (82:18)
A3 (89:11)
A4 (82:18)
A5 (92:8)
A6 (94:6)
A7 (94:6)
59
47
55c
64
64
34
L2
L3
L4
L5
L6
L7
94
92
34d
82
63
74
a The diastereomeric ratio determined by GC-MS is shown in parentheses. b Isolated yield after purification by recrystallization of the corresponding
hydrochloride salt. c Purification by chromatography. d Yield not optimized.
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Org. Lett., Vol. 7, No. 8, 2005

Figure 2. Comparison of the kinetics of the catalysts resulting
from the corresponding ligands in the Ir-catalyzed allylic amination
with benzylamine.
Figure 3. Comparison of the kinetics of the catalysts resulting
from the corresponding ligands in the Ir-catalyzed allylic alkylation
with sodium dimethylmalonate.
kinetics of L3 is much slower than L2, giving a slope similar
to that of L1 (Figure 3).
For comparison, we studied the congener featuring the
1-naphthyl moiety L7 used by Hartwig4f,g which gave a
higher reaction rate than L2 but less impressive than L6.
A similar study was conducted on the allylic alkylation.
A comparable trend was detected. Ligands bearing either no
substituent at all (L1) or a methoxy group in the para position
(L3) were the slower ones. The two pseudo-C2-symmetrical
ligands, L4 and L5, showed a slight improvement compared
to L1 and L3, although we expected L5 to be much faster.
Ligands L2 and L6 showed impressive results, keeping the
trend we observed in the amination experiment. Once again,
L7 was less efficient in terms of kinetics.
Concerning the enantio- or regioselectivities, all the ligands
gave results in the same range (92-99% ee, Figure 4),
suggesting that only the kinetics of the reaction is dramati-
cally modified by the steric bulk of the amine moiety of the
ligand. Nevertheless, ligand L6 gave the best enantioselec-
tivities for both reactions, 98.3 and 99.1%.
We then looked to the influence of a sole o-methoxy
substituent; the reaction showed an intermediate kinetic slope
between L2 and L1, which seems to be in accord to the
calculations. To confirm an eventual coordination role of the
substituent, we replaced the methoxy by a simple methyl
group in the ortho position as in L5. This ligand gave a
kinetic slope as close to the one of L2, suggesting that our
first postulated model might be wrong. To confirm this
statement, we synthesized the C2-symmetrical ligand L6
bearing two o-methyl substituents. This ligand gave a
spectacular improvement of the kinetics of the reaction,
allowing its completion in less than 3 h at room temperature!
(6) Tissot-Croset, K.; Polet, D.; Alexakis, A. Angew. Chem., Int. Ed.
2004, 43, 2426-2428.
(7) Alexakis, A.; Polet, D. Org. Lett. 2004, 20, 3529-3532.
(8) Lipowsky, G.; Miller, N.; Helmchen, G. Angew. Chem., Int. Ed. 2004,
43, 4595-4597.
(9) This argument was used to justify a reaction acceleration effect in
polar solvents. See ref 3 for details.
This study shows that the o-methoxy group seems too
remote to play any coordination role, but rather a steric effect,
as ligand L6 bearing no oxygen but a methyl group at the
(10) Work in progress.
(11) Alexakis, A.; Gille, S.; Prian, F.; Rosset, S.; Ditrich, K. Tetrahedron
Lett. 2004, 45, 1449-1451.
Org. Lett., Vol. 7, No. 8, 2005
1623

the neighboring aryl group13 of the amine part cannot be
excluded, and further studies are currently in progress.
In conclusion, these results give interesting insights
concerning slight changes in the structure of the ligands to
improve not only the enantioselectivity but also the kinetics
of both reactions.
Acknowledgment. We thank Karine Tissot-Croset,
Ste´phane Rosset, and Caroline Falciola for help, the BASF
Co. for the generous gift of chiral primary amines, and the
Swiss National Research Foundation No. 200020-105368 and
COST action D24/0003/01 (OFES contract Nï. C02.0027)
for financial support.
Supporting Information Available: Experimental de-
tails, chromatograms, and spectral data for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 4. Recapitulative comparison of the ee’s (%) resulting from
the Ir-catalyzed allylic amination with benzylamine and alkylation
with sodium dimethylmalonate with ligands L1-L7.
OL050350W
same position gave even more spectacular results. Such steric
effects are well-known with phosphorus ligands where the
ligand cone angle θ plays a crucial role.12An η2 effect of
(12) Tolman, C. A. Chem. ReV. 1977, 77, 313-348.
(13) Lloyd-Jones, G. C.; Stephen, S. C.; Murray, M.; Butts, C. P.;
Vyskocil, S.; Kocovsky, P. Chem. Eur. J. 2000, 6, 4348-4357.
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Org. Lett., Vol. 7, No. 8, 2005