initial insertion of the metal complex into the distal bond of
the alkylidenecyclopropane to give palladacyclobutane A
followed by rearrangement to the intermediate C. Reductive
elimination of this compound would provide the cycloadduct
2. The rearrangement A-C could occur either directly or
through the intermediacy of isomer B.5
Given that the cycloaddition reaction involves the genera-
tion of a stereocenter, it appeared reasonable to investigate
the prospect of inducing asymmetry by using an appropriate
chiral ligand. The electronic similarity between phosphites
and phophoramidites, coupled to the increasing demonstra-
tion of the utility of this latter type of ligands in several
catalytic asymmetric transformations,6 prompted us to in-
vestigate their behavior in our reaction system.
This investigation has led to the discovery of new ligands
that accelerate the cycloaddition process to the extent that it
can be carried out in a truly practical and efficient manner
using low catalyst loadings.
Figure 1. Ligands used in the study.
The initial assays were carried out with the well-known
binaphthyl-containing phosphoramidite L1, which has been
shown to give interesting results in several metal-catalyzed
asymmetric C-C bond-forming reactions.6g-k Although the
asymmetric induction results obtained in the cycloaddition
of 1a were poor (Table 1), we were surprised to observe a
with the appropriate diol in the presence of Et3N.7a Ligand
L5 was better prepared in two steps by refluxing the diol in
neat phosphorus trichloride and, after removal of the remain-
ing phosphorus trichloride, addition of diisopropylamide (see
the Supporting Information).7b,c
The acceleration effects were studied on substrate 1b
because it is easily distinguishable from the product 2b by
gas chromatography (GC). The reactions were performed in
refluxing dioxane (50 mM) using 1 mol % of Pd2(dba)3 and
4 mol % of the ligand. The conversion results are represented
in Figure 2. It can be observed that the reaction rate with
ligands L1 and L2 is quite similar and considerably higher
than that observed with P(i-PrO)3, which apparently requires
an induction period. Replacement of the biphenol by two
2-propanol groups generates a ligand (L3) that performs
considerably worse. Remarkably, removal of the branching
methyl groups from the benzylamino moieties of L2 leads
to a marked decrease in the accelerating power of the ligand
(ligand L4). On the other hand, the use of L5, which features
a bis(isopropyl)amine instead of the bis(1-phenylethyl)amine
of L2, produces a less dramatic but still significant decrease
in the reaction rate. We also observed that in toluene the
rate differences between the best ligands and P(i-PrO)3 are
even greater than those observed in dioxane.
Table 1. Enantioselectivity Observed in the Pd-Catalyzed
Cycloaddition Using Phosphoramidite Ligand L1
entry
solvent
time (min)a
T (°C)
eeb (%)
1
2
dioxane
toluene
15
180
101
80
8
26
a Time required for complete consumption of the starting material.
b Analyzed by chiral HPLC (Chiralcel OJ, i-PrOH/Hex 1:9, 0.5 mL/min).
substantial acceleration of the cycloaddition process with
respect to reaction rate achieved using the standard P(i-PrO)3.
We therefore decided to further analyze this accelerating
effect by examining the performance of different phosphora-
midites (Figure 1).
The synthesis of ligands L2, L3, and L4 was accomplished
according to published procedures by heating the required
amine with a stoichiometric amount of phosphorus trichloride
in toluene (70 °C) followed by room-temperature treatment
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Org. Lett., Vol. 7, No. 25, 2005