C O M M U N I C A T I O N S
Scheme 2. Pd-Catalyzed Allylic Alkylation of Unhindered
Table 1. Pd-Catalyzed Allylic Alkylation of S1 with Ligands 1 and
2a
Substrates S2 and S4-S6 with Ligands 1 and 2
entry
ligand
Nu-H
% convb (min)
% eec
1
2
3
4
5
6
7
8
9d
1a
1b
1c
1d
1e
1f
1g
2
1b
CH2(COOMe)2
CH2(COOMe)2
CH2(COOMe)2
CH2(COOMe)2
CH2(COOMe)2
CH2(COOMe)2
CH2(COOMe)2
CH2(COOMe)2
CH2(COOMe)2
71 (5)
100 (5)
84 (5)
>99 (S)
>99 (S)
>99 (S)
>99 (S)
42 (S)
95 (5)
100 (30)
100 (30)
100 (30)
100 (5)
100 (25)
95 (S)
99 (S)
99 (R)
99 (S)
Scheme 3. Pd-Catalyzed Allylic Alkylation of S3 and S7 Using
Ligand 1a
a 0.5 mol % [Pd(π-C3H5)Cl]2, 1.1 mol % ligand, CH2Cl2 as solvent, BSA/
KOAc as base, room temperature. b Measured by 1H NMR. Reaction time
in minutes shown in brackets. c Determined by HPLC. d S1/Pd ) 1000.
Bulky substituents in the ortho positions of the biphenyl phosphite
moiety are needed for high enantioselectivity (entries 4 and 6 versus
5). Moreover, the substituents in the para positions of the biphenyl
phosphite moiety have a slight but important effect on both activity
and enantioselectivity. Activities and enantioselectitivies are there-
fore highest when tert-butyl groups are present at both the ortho
and para positions of the biphenyl phosphite moiety.
The use of ligand 2, whose configuration of the oxazoline moiety
is opposite to that of ligands 1, produced the same high enantio-
selectivity, though in the R product (entry 8). This new family of
ligands therefore offers excellent enantioselectivities in both enan-
tiomers of the product.
We also performed the reaction at low catalyst concentration
using ligand 1b (entry 9). The excellent enantioselectivity (99%
(S) ee) and activity (100% conversion after 25 min at room
temperature, TOF > 2400 mol‚(mol‚h)-1) were maintained.
We then tested ligands 1 and 2 in the Pd-catalyzed allylic
amination of S1 with benzylamine (eq 1b). We observed that the
catalytic performance follows the same trend as that for the allylic
alkylation of S1. Both enantiomers of the product can also be
obtained with high enantioselectivity (ee’s up to 99%). Although,
as expected, the activities are lower than that in the alkylation
reaction, they are much higher than when PHOX ligands were used
(reaction time usually 96 h).5
The enantioselectivity in unhindered linear and cyclic substrates
is usually more difficult to control. For high ee’s to be achieved, it
is crucial that ligands create a small chiral pocket around the metal
center, mainly because of the presence of less sterically syn
substituents.1 The development of enantioselective catalysts for both
hindered and unhindered substrates has been a challenge because
none of the existing ligands is able to tune the size of the chiral
pocket adequately.6 The presence of the bulky biphenyl in the
phosphite moiety in ligands 1 and 2, which are known to be flexible
and to provide large bite angles, can therefore also provide excellent
results for unhindered substrates. We therefore decided to test the
new phosphite-oxazoline ligands in the Pd-catalyzed allylic
alkylation of 1,3-dimethyl-3-acetoxyprop-1-ene S4 substrate and
several cyclic substrates S2, S5, and S6, which are less sterically
demanding (Scheme 2).
developed to date favor the formation of the achiral linear product
rather than the desired branched isomer.7 The catalytic system
containing ligand 1a produced under unoptimized conditions the
desired branched isomers as the major products. Note the excellent
regio- and enantioselectivity obtained with substrate S7. These
results are among the best reported so far.
In short, we have designed and synthesized a new family of
readily available phosphite-oxazoline ligands that shows excellent
reaction rates (TOF’s up to >2400 mol‚(mol‚h)-1) and enantiose-
lectivities (ee’s up to >99%) and, at the same time, shows a broad
scope for different substrate types. The reason for this is that the
presence of π-acceptor flexible bulky biphenyl phosphite moieties
allows the creation of a smaller and, at the same time, more flexible
chiral pocket.
Acknowledgment. We thank the Spanish Ministerio de Edu-
cacio´n, Cultura y Deporte (BQU2001-0656), the Spanish Ministerio
de Ciencia y Tecnologia (Ramon y Cajal Fellowship to O.P.), and
the Generalitat de Catalunya (Distinction to M.D.).
Supporting Information Available: Experimental procedures for
the preparation of ligands 1 and 2 and for the allylic substitution
reactions, the catalytic alkylation results of S2, S4-S6, and the
amination of S1 using ligands 1 and 2. This material is available free
References
(1) For recent reviews, see: (a) Trost, B. M.; van Vranken, D. L. Chem.
ReV. 1996, 96, 395. (b) Johannsen, M.; Jorgensen, K. A. Chem. ReV. 1998,
98, 1869. (c) Pfaltz, A.; Lautens, M. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer-
Verlag: Berlin, 1999; Vol. 2, Chapter 24. (d) Helmchen, G.; Pfaltz, A.
Acc. Chem. Res. 2000, 33, 336. (e) Trost, B. M.; Crawley, M. L. Chem.
ReV. 2003, 103, 2921.
(2) (a) Die´guez, M.; Jansat, S.; Go´mez, M.; Ruiz, A.; Muller, G.; Claver, C.
Chem. Commun. 2001, 1132. (b) Pa`mies, O.; van Strijdonck, G. P. F.;
Die´guez, M.; Deerenberg, S.; Net, G.; Ruiz, A.; Claver, C.; Kamer P. C.
J.; van Leeuwen, P. W. N. M. J. Org. Chem. 2001, 66, 8867.
(3) Bulky biphenyl phosphites are known to provide larger bite angles than
phosphines. The opening of the bite angle is necessary for high chiral
recognition in the Pd-catalyzed alkylation reactions. Trost, B. M.; van
Vranken, D. L.; Bingel, C. J. Am. Chem. Soc. 1992, 114, 9327.
(4) The flexibility that offers the biphenyl moiety can be used to fine-tune
the chiral pocket formed upon complexation.
Interestingly, for these sterically undemanding substrates, high
reaction rates (TOF’s > 200 mol‚(mol‚h)-1) and enantioselectivities
(ee’s up to 99%), in both enantiomers of the product, were also
achieved.
Encouraged by the excellent results, we also tested ligand 1a in
the allylic alkylation of more demanding substrates: the mono-
substituted linear substrates S3 and S7 (Scheme 3). For these
substrates, the development of highly regio- and enantioselective
Pd catalysts still represents a challenge. Most of the Pd catalysts
(5) von Matt, P.; Loiseleur, O.; Koch, G.; Pfaltz, A.; Lefeber, C.; Feucht, T.;
Helmchen, G. Tetrahedron: Asymmetry 1994, 5, 573.
(6) So far only the diphospholane developed by Osborn and co-workers have
provided good ee’s for substrates S1, S2, and S4. Dierkes, P.; Randechul,
S.; Barloy, L.; De Cian, A.; Fischer, J.; Kamer, P. C. J.; van Leeuwen, P.
W. N. M.; Osborn, J. A. Angew. Chem., Int. Ed. 1998, 37, 3116.
(7) For recent successful applications of Pd catalysts, see: (a) Pre´toˆt, R.; Pfaltz,
A. Angew. Chem., Int. Ed. 1998, 37, 323. (b) Hilgraf, R.; Pfaltz, A. Synlett
1999, 1814. (c) You, S.-L.; Zhu, X.-Z.; Luo, Y.-M.; Hou, X.-L.; Dai,
L.-X. J. Am. Chem. Soc. 2001, 123, 7471.
JA0425738
9
J. AM. CHEM. SOC. VOL. 127, NO. 11, 2005 3647