Pd-catalyzed enantioselective allyl-allyl cross-coupling

Article abstract of DOI:10.1021/ja105161f

The Pd-catalyzed cross-coupling of allylic carbonates and allylB(pin) is described. The regioselectivity of this reaction is sensitive to the bite angle of the ligand, with small-bite-angle ligands favoring the branched substitution product. This mode of

Full text of DOI:10.1021/ja105161f

Published on Web 07/15/2010
Pd-Catalyzed Enantioselective Allyl-Allyl Cross-Coupling
Ping Zhang, Laura A. Brozek, and James P. Morken*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received June 13, 2010; E-mail: morken@bc.edu
in prompting the bis(η1-allyl) bonding mode and that, if the allyl groups
Abstract: The Pd-catalyzed cross-coupling of allylic carbonates
and allylB(pin) is described. The regioselectivity of this reaction
is sensitive to the bite angle of the ligand, with small-bite-angle
ligands favoring the branched substitution product. This mode of
regioselection is consistent with a reaction that operates by a 3,3′
reductive elimination reaction. In the presence of appropriate
chiral ligands, this reaction is rendered enantioselective and
applies to both aromatic and aliphatic allylic carbonates.
are able to rapidly isomerize at some point on the reaction pathway,
the least hindered bis(η1-allyl) (C) might predominate when substitution
is present. In such a situation, the selectivity for formation of the chiral,
branched 3,3′ elimination product relative to the linear 1,1′ elimination
product should be sensitive to the bite angle of the ligand, and this
feature provides a potential control element for the reaction.10
Inspired by the observations of Miyaura11a and others,11b,c our
initial experiments probed the reactivity of allylB(pin) and allylic
carbonates. Efficient reactivity was observed with carbonate 1. As
shown in Table 1, in the presence of Pd(0) and bidentate ligands,
the allyl-allyl cross-coupling reaction occurs, and with small-bite-
angle ligands, complete conversion and high selectivity is observed.
From the data in Table 1, it is clear that smaller-bite-angle ligands
favor the branched product, whereas larger-bite-angle ligands are
nonselective. This is consistent with the reaction proceeding through
an intermediate such as C (Scheme 1); the increased C1-C1′
separation that accompanies small-bite-angle ligands12 may disfavor
the 1,1′ elimination pathway relative to the 3,3′ path.13
The Pd-catalyzed cross-coupling of organic electrophiles with
organometallic reagents, especially organoboron derivatives, is
broadly developed and has made a significant impact on the way
complex molecules are prepared.1 One exception to this generaliza-
tion is the cross-coupling of substituted allylmetal reagents. This
reaction has received less attention but holds significant promise
for asymmetric synthesis;2 recently reported Pd-catalyzed enanti-
oselective couplings of crotyl boronates and aryl electrophiles are
illustrative.3 Similarly, cross-coupling of allylmetal reagents with
allyl electrophiles is attractive because it has the capacity to establish
two new stereocenters with concomitant formation of an sp3-sp3
carbon-carbon bond.4 This catalytic reaction is not well developed
either, perhaps because of the propensity for π-allyl intermediates
to undergo ꢀ-hydride elimination5 (delivering 1,3-dienes) and
perhaps because these reactions often lack regioselectivity or favor
achiral products. Indeed, unlike the isoelectronic decarboxylative
allylation of allyl enol carbonates6 and the Tsuji-Trost reaction
with preformed enolates,7 allyl-allyl coupling does not benefit from
an inherent regiocontrol bias. In this report, we present a paradigm
for regiocontrol in allyl-allyl coupling reactions and use it to
establish highly regio- and enantioselective catalytic variants.
Recent studies in our laboratory have focused on the transition-
metal-catalyzed enantioselective addition of allylboronates to unsatur-
ated carbonyls.8 These reactions proceed by way of oxygenated
bis(allyl)metal species, with a 3,3′ reductive elimination being respon-
sible for construction of the C-C bond. The 3,3′ reductive elimination
mechanism, as put forward by Echavarren,4j,9 operates when coordina-
tion of a ligand to a bis(allyl)metal species causes both allyl groups to
adopt the η1 bonding mode (as in B in Scheme 1) instead of the more
common η3 mode (as in A). We surmised that in the case of simple
allyl-allyl cross-coupling, bidentate ligands would be most effective
Table 1. Pd-Catalyzed Branch-Selective Cross-Coupling
entry
ligand
bite anglea
% yieldb
branched/linearc
1
2
3
4
5
6
7
PPh3
dpp-benzene
dppe
dppp
dppf
-
83
85
91
96
96
70
77
80
43
77
58
1:>20
97:3
98:2
97:3
94:6
dppb
DPEphos
98
102
38:62
72:28
a Ligand-preferred bite angle (see ref 10b). b Yield of purified
material. c Determined by GC.
With an effective means of controlling the regioselectivity in
allyl-allyl cross-coupling reactions in hand, a survey was under-
taken to gauge the ability of small-bite-angle chiral bidentate li-
gands to control the enantioselectivity in the process. 2,2′-Bis(di-
furylphosphino)-6,6′-dimethoxybiphenyl14 (A in Table 2) was found
to deliver the allyl-allyl cross-coupling product with high regio-
and enantioselectivity. As depicted in Table 2, the reaction is
effective with a number of allyl carbonates, generally delivering
the branched substitution product with excellent regio- and enan-
tioselectivity. As shown in entries 1 and 2, tert-butyl and methyl
carbonates can be used interchangeably in the reaction. It is also
noteworthy that the corresponding internal racemic carbonate (entry
3) reacts with levels of selectivity that are comparable to those of
primary-alcohol-derived substrates (entries 1 and 2). This observa-
tion has mechanistic implications (see below) and is also of practical
importance: substrates such as that depicted in entry 3 can be more
Scheme 1
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10.1021/ja105161f  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Enantioselective Allyl-Allyl Cross-Couplinga
strates (additional data not shown). Currently, one limitation of the
reaction is that an electron-deficient allyl electrophile was observed to
react with diminished levels of selectivity (entry 8).
A notable observation with respect to synthetic utility is that
aliphatic substrates also participate in the allyl-allyl coupling
reaction: while the example in entry 10 occurred with moderate
selectivity using (R)-MeO-furyl-BIPHEP, the selectivity could be
improved substantially by employing (R,R)-QuinoxP*15 as the
ligand. The problematic low yield in entry 10 was easily ameliorated
by employing the regioisomeric internal carbonate depicted in entry
11. It merits mention that linear alkyl substrates as well as those
bearing allylic and homoallylic oxygen functionality are readily
processed in the reaction (entries 12-14) and deliver the branched
product efficiently and with good regio- and enantioselectivity.
The observation that isomeric allylic carbonates (i.e., entries 1-3,
10, and 11) react with similar levels of enantioselectivity suggests
that oxidative addition of the allyl carbonate to Pd(0) provides a
common intermediate (such as D in Scheme 2). Subsequent reaction
with allylB(pin) might occur by transmetalation from boron to Pd
followed by inner-sphere 3,3′ reductive elimination, as mentioned
above (see C in Scheme 2). Alternatively, the reaction might occur
by backside outer-sphere attack of the allylboronate on a η3-
allyl-Pd complex (E in Scheme 2).16
Scheme 2
To distinguish between the above-described mechanisms, isotopi-
cally labeled allylB(pin) was employed as the substrate in the
allyl-allyl coupling reaction (Scheme 3). When this experiment was
conducted in the presence of the chiral catalyst, the deuterium label
was found at both allyl termini in the reaction product (recovered
allylBpin was unscrambled). Since nucleophilic addition involving
allylmetal reagents often occurs by an SE2′ reaction mechanism,17 it
might be expected that the outer-sphere pathway would proceed
without isotope scrambling. Alternatively, SE2′ transmetalation8b,18
followed by equilibration of the bis(allyl)Pd complex may account
for the reaction outcome. Along these lines, it should be noted that
while four-coordinate bis(allyl)Pd complexes most often adopt the
bis(η1) bonding mode (such as in C in Scheme 2), (η1-methallyl)(η3-
methallyl)Pd(dcpe) is a known compound whose existence supports
the accessibility of intermediates required for isotope scrambling.19
Scheme 3
a Unless otherwise noted, reactions employed 1.2 equiv. of
allylB(pin). b Reaction with 1.5 equiv of allylB(pin). c Reaction with 2.0
equiv allylB(pin) for 36 h. d With the addition of 1.2 equiv of Cs2CO3.
accessible than substrates such as in entries 1 and 2. Entries 4-7 and
9 show that sterically encumbered substrates and those possessing
halogens or heteroatoms are also suitable partners for the reaction.
Remarkably, as the example in entry 9 indicates, unactivated alcohols
are reactive leaving groups in the coupling reaction, although this
feature currently appears to be most effective with electron-rich sub-
To further validate the proposed inner-sphere reductive elimination
pathway, enantiomerically enriched (S)-Z-10 (Scheme 4) was prepared
and subjected to the asymmetric cross-coupling with (R)-MeO-furyl-
BIPHEP as the ligand. This reaction provided (S)-E-11 as the sole
product in 91% ee. With the assumption that conversion of (S)-Z-10
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C O M M U N I C A T I O N S
to the derived π-allyl complex occurs by an anti displacement of the
leaving group (to give F), as is known to occur for related systems,20
it can be concluded that (S)-E-11 can only be produced by C-C bond
formation syn to palladium after the metal has migrated to the opposite
face of the cinnamyl-derived allyl fragment (G or related); this outcome
is consistent only with an inner-sphere reductive elimination.
Supporting Information Available: Experimental procedures and
characterization data. This material is available free of charge via the
Internet at http://pubs.acs.org.
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Scheme 4
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Scheme 5
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In conclusion, a highly regio- and enantioselective allyl-allyl coupling
reaction has been described. The regiochemical outcome of the reaction
and the described isotope-labeling experiments are consistent with a
pathway involving 3,3′ reductive elimination of bis(allyl)Pd complexes.
An important feature of the reaction is that it provides enantiomerically
enriched vicinal π-π systems that are not accessible by the Cope
rearrangement, and this may find use in organic synthesis.
Acknowledgment. Support by the NIGMS (GM-64451) and
the NSF (DBI-0619576, BC Mass Spectrometry Center) is gratefully
acknowledged. P.Z. is grateful for a LaMattina Fellowship. We
thank Frontier Scientific for a generous donation of allylB(pin).
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