Chasing the proton culprit from palladium-catalyzed allylic amination

Article abstract of DOI:10.1021/ja076659n

We have found that the addition of base has a significant effect on palladium-catalyzed allylic amination. The long-standing problem of controlling the branched-to-linear ratio has been solved. In the presence of DBU and inexpensive, readily available ligands, palladium-catalyzed allylation proceeds under kinetic control, leading to high branched selectivity. Given the widespread utility of palladium-catalyzed allylic amination, we expect that these findings will be relevant in many areas ranging from asymmetric catalysis to target-oriented synthesis. Copyright

Full text of DOI:10.1021/ja076659n

Published on Web 10/26/2007
Chasing the Proton Culprit from Palladium-Catalyzed Allylic Amination
Igor Dubovyk, Iain D. G. Watson, and Andrei K. Yudin*
DaVenport Research Laboratories, Department of Chemistry, The UniVersity of Toronto, 80 St. George Street,
Toronto, Ontario, Canada M5S 3H6
Received September 4, 2007; E-mail: ayudin@chem.utoronto.ca
Transition-metal-catalyzed allylic amination has long been an
area of intense research.1 Allylamines have previously been prepared
using iridium2 and rhodium3 catalysts with high selectivities for
the branched products. On the other hand, the use of palladium in
this chemistry has been known to produce linear allylamines with
few notable exceptions.4 This phenomenon has been obscure for
Figure 2. Base effect on selectivity in allylic amination.
some time. The goal of this contribution is to shed light on this
long-standing problem and to evaluate ways of exercising control
Table 1. Ligand Screen for Benzylamine and Acetate 2b
over selectivity with palladium catalysts.
entry
ligand
b/l
We recently demonstrated an instructive aberration in palladium-
catalyzed allylic amination: unsubstituted aziridines were found to
give preferential formation of branched allylated products.5 Mecha-
nistic investigations indicate that amines other than aziridines
undergo branched/linear (b/l) isomerization to form the thermody-
namically more stable linear products.5,6 It was found that protic
acid generated during the reaction is the prerequisite for product
isomerization.5 Palladium coordination to the double bond of the
protonated allylamine initiates ionization of the kinetically favored
branched product (Figure 1). We consequently sought conditions
under which the proton can be scavenged without detrimental effect
on catalytic turnover such that the linear product formation can be
suppressed.
1
2
3
P(OEt)3
rac-BINAP
Cy2P(o-biphenyl)
6:1
1:2
99:1
acetate. When DBU is present, the branched monoallylated product
does not isomerize.2b,7 The use of a substoichiometric amount of
DBU (25%) was found to preferentially give the linear product.
While it appeared possible to control the b/l ratio with trisub-
stituted allyl acetates, the reaction outcome with disubstituted
substrates was not as straightforward. The presence of DBU is a
necessary but not a sufficient requirement to favor the formation
of branched products from disubstituted allyl acetates. The reaction
outcome strongly depends on both the ligand and the amine.
Triethylphosphite, which favors the formation of branched product
with prenyl acetate 2a (Table 1), gives a 6:1 b/l ratio with acetate
2b. Bidentate ligands give lower b/l ratios with 2b. Luckily,
2-(dicyclohexyl)biphenyl phosphine8 significantly improved selec-
tivity giving greater than 99:1 b/l ratio for this challenging substrate.
Allyl acetate 2c gave lower selectivity (entry 3, Table 2), but the
same general trend prevailed.
Figure 1. Branched-to-linear isomerization in allylic amination.
Extensive screening of a variety of bases was performed in order
to affect the b/l ratio (see Supporting Information). Irrespective of
their pKa values, the majority of these additives either destroyed
the starting acetate, arrested catalytic turnover, or had no effect.
Delightfully, DBU struck the right balance: it produced branched
products with high selectivities and without detrimental effects.
Table 2 shows b/l ratios and yields for secondary as well as primary
aliphatic amines. The developed conditions are well suited for
challenging nonhindered aliphatic amines, known to exhibit low
selectivities.5a In our system, benzylamine proved to be among the
most interesting substrates: in the absence of DBU, a linear
bisallylated product 3g was formed, while in the presence of DBU,
the branched isomer 3f was the major product with no bisallylation
byproducts (Figure 2). The latter fact supports the idea that in the
absence of DBU the kinetic branched product has to undergo
isomerization before it can react with another equivalent of allyl
Figure 3. Pd(II) intermediates in the course of allylic amination.
The strong preference for branched products in the presence of
DBU can be explained by considering the palladium intermediates
shown in Figure 3. After Pd(0) attack on trisubstituted prenyl acetate
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J. AM. CHEM. SOC. 2007, 129, 14172-14173
10.1021/ja076659n CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Substrate Scope for Base-Controlled Allylic Amination
a Cy2P(o-biphenyl) ligand was used. b GC yield. c No DBU was added. d Contaminated with 10% of P(OEt)3 that co-distills at 85 °C at 0.9 mmHg.
in THF, the resulting intermediate exists predominantly as the linear
References
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smaller extent. DBU keeps the reaction under kinetic control, but
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In summary, we have shown that the presence of DBU in
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Given the widespread utility of palladium-catalyzed allylic ami-
nation, we expect that these findings will be relevant in areas
ranging from asymmetric catalysis to target-oriented synthesis.
Finally, chasing the proton culprit from palladium catalysis
using well-tuned base additives may operate in other catalytic
processes. It is likely that a search for such reactions will lead to
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since a proton can sometimes act as the catalyst, thus veiling metal
activity.9
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Acknowledgment. We thank NSERC for financial support.
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Supporting Information Available: Experimental procedures and
characterization data for all unknown compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JA076659N
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