Palladium-catalyzed hydroarylation of 1,3-dienes with boronic esters via reductive formation of π-Allyl palladium intermediates under oxidative conditions

Article abstract of DOI:10.1021/ja105010t

A palladium-catalyzed reductive cross-coupling of 1,3-dienes with boronic esters in which a π-allyl Pd species is generated directly from a 1,3-diene via a Pd-catalyzed aerobic alcohol oxidation is reported. Both the scope of the process and the origin of a highly selective 1,2-addition are discussed.

Full text of DOI:10.1021/ja105010t

Published on Web 07/08/2010
Palladium-Catalyzed Hydroarylation of 1,3-Dienes with Boronic Esters via
Reductive Formation of π-Allyl Palladium Intermediates under Oxidative
Conditions
Longyan Liao and Matthew S. Sigman*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-0850
Received December 4, 2009; E-mail: sigman@chem.utah.edu
Table 1. Optimization of the Hydroarylation of 1a
Abstract: A palladium-catalyzed reductive cross-coupling of 1,3-
dienes with boronic esters in which a π-allyl Pd species is
generated directly from a 1,3-diene via a Pd-catalyzed aerobic
alcohol oxidation is reported. Both the scope of the process and
the origin of a highly selective 1,2-addition are discussed.
entry
Pd source
x
y
T (°C) % conv.a % 3ab
3a/4a
Since the first report in 1957,1 the π-allyl complexes of palladium
have played a central role in Pd catalysis because of the ease in
which these complexes undergo nucleophilic substitution.2 Clas-
sically, π-allyl Pd species are most commonly generated from
reaction of Pd(0) with an allyl fragment containing a leaving
group2c,3 or from nucleophilic addition to a 1,3-diene promoted
by Pd(II).2e,4 More recently, efforts to directly access these
intermediates via allylic oxidation have been reported.5 On the basis
of our programmatic focus on the development of Pd-catalyzed
alkene hydrofunctionalization reactions coupled to the reduction
of O2,6 we became interested in accessing π-allyl Pd species
reductively directly from 1,3-dienes. These substrates have per-
formed rather poorly in our previous reports.6 To accomplish this,
we hypothesized that a Pd hydride B formed from the oxidation of
an alcohol could be intercepted by a 1,3-diene, yielding the desired
π-allyl intermediate C (Scheme 1).7 Herein we report the successful
generation of these intermediates from dienes and an in situ-formed
Pd hydride and their subsequent cross-coupling with aryl boronic
esters to accomplish a highly regioselective diene hydroarylation
reaction using O2 as the terminal oxidant.
1
2
3
4
5
[Pd(SiPr)Cl2]2
Pd[(-)-sparteine]Cl2
Pd[(-)-sparteine]Cl2 20
Pd[(-)-sparteine]Cl2 20 0.5
Pd[(-)-sparteine]Cl2 20 0.5
6
6
6
6
6
55
55
55
55
75
7
70
58
96
>99
3
42
45
63
76
5:1
22:1
19:1
>99:1
25:1
a Measured by GC using an internal standard. b GC yield using an
internal standard.
products was >99:1 on the basis of GC analysis. Removal of exogenous
(-)-sparteine led to rapid decomposition of the catalyst. Therefore,
the amount of excess sparteine was increased, with an observed
improvement in selectivity and yield of the desired product (entry 3).
t
Decreasing the amount of BuOK (entry 4) as well as raising the
temperature (entry 5) led to a noticeable increase in the product yield.
Use of 3 equiv of the boronic ester was required because of the
consumption of this reagent through oxidative homocoupling and
formation of phenol by hydrogen peroxide produced from the reduction
of O2.6c It should be noted that tBuOK was required for adequate yields
of product.
Scheme 1. Proposed Mechanism for Hydroarylation of 1,3-Dienes
With this optimized catalyst system in hand, the substrate scope
was explored (Table 2). First, the nature of the arylboronic ester
was evaluated using diene 1a (products 3a-h). Isolated yields were
generally good to excellent, and all of the reactions were highly
1
regioselective for the 1,2-addition product (>95:5 by H NMR).
o-Substitution is allowed (3b), while the electronic nature of the
boronic ester has a minimal impact on the yield of the reaction, in
contrast to our previous reports (3c-h).6c This is highlighted by
the incorporation of an ester (3e), a nitrile (3g), and an acid-sensitive
acetal group (3h). Several substituted diene derivatives in the
reaction with boronic ester 2a were also examined. Moderate to
good yields were achieved with simple hydrocarbons (3i-l). An
electron-rich aryl-substituted diene gave the corresponding product
in high yield (3m), and a TBS protected alcohol was tolerated using
this catalyst system, giving the product in excellent yield (3n). It
should be noted that acceptable yields were found only when using
arylboronic esters.
Diene 1a and boronic ester 2a were selected as the substrates for
optimization and initially evaluated under the conditions previously
reported for styrene hydroarylation using [Pd(SiPr)Cl2]2 as the catalyst
(Table 1, entry 1).6 This catalyst system performed poorly with little
conversion of the substrate, possibly because of the excellent stability
of N-heterocyclic carbene allyl palladium species.8 Therefore, we
explored the use of Pd[(-)-sparteine]Cl2, whose π-allyl complexes
have previously been structurally characterized and successfully used
in nucleophilic addition chemistry.9 The use of this catalyst led to a
significant improvement in conversion and GC yield of the desired
product. It is important to note that the ratio of the 1,2- to 1,4-addition
9
10.1021/ja105010t  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 10209–10211 10209

C O M M U N I C A T I O N S
Table 2. Substrate Scopea
Figure 1. Linear free-energy relationship between Charton steric parameters
and the logarithm of the ratio of regioisomers (1,2- to 1,4-addition).
substituents on the dienes.12 A linear free-energy relationship was
observed, consistent with steric effects dominating the selectivity
in this reaction (Figure 1). However, the substrate containing a
cyclohexyl substituent clearly did not fit in the correlation, and the
reason for this is not obvious.
a Yields are average isolated yields of at least two experiments. A
>95:5 ratio of the 1,2- to 1,4-hydroarylation products was measured by
1H NMR spectroscopy.
In summary, we have developed a novel approach for the
hydroarylation of 1,3-dienes by accessing π-allyl intermediates
directly using a coupled aerobic alcohol oxidation to access a Pd
hydride. The scope of the process shows wide tolerance of
functional groups on the boronic ester and on the diene. Moreover,
high selectivity was observed for the 1,2-addition product and has
been shown to have a steric origin. Although an enantioenriched
chiral ligand was used in this chemistry, only poor enantioselectivity
was achieved (<20% ee). Therefore, future work will be focused
on identification of new ligand classes to promote this reaction with
high enantioselectivity.
Scheme 2. Reactions To Probe the Intermediacy of a π-Allyl Pd
Species
Acknowledgment. This work was supported by the National
Institutes of Health (Grant NIGMS R01 GM3540). M.S.S. thanks
the Dreyfus Foundation (Teacher-Scholar) and Pfizer for their
support.
Classically, addition to π-allyl palladium complexes leads to a
mixture of R- (1,2-addition in our case) and γ-coupled products.10
The observation that high selectivity for the 1,2-addition product
was found is not only synthetically attractive but also prompted us
to investigate the intermediacy of a π-allyl Pd species. Therefore,
a series of reactions was carried out. First, both stereochemically
pure Z and E diene isomers of 1a were submitted to the reaction
conditions (Scheme 2). Although the observed rate of conversion
for the E isomer was 1.6 times higher than that of the Z isomer,
both led to only a single isomeric product, suggesting a π-allyl Pd
intermediate. The Z isomer did not appreciably form the E isomer
under the reaction conditions. Second, the reactions of conjugated
diene 1h and skipped diene 1i both gave the same hydroarylation
product, again consistent with a presumed π-allyl Pd intermediate.
Conversion of 1i to ∼10% 1h was found by GC during the reaction,
consistent with the formation of a Pd hydride. Finally, an experiment
was carried out in which diene 1a was mixed with Pd[(-)-
sparteine]Cl2 in the presence of isopropyl alcohol for 1 h at 60 °C,
wherein a composition consistent with the [(-)-sparteine]PdII(π-
allyl)(Cl) complex was confirmed by ESI-HRMS.11
Supporting Information Available: Experimental procedures and
characterization data for substances. This material is available free of
charge via the Internet at http://pubs.acs.org.
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