Palladium-catalyzed allylic cross-coupling reactions of primary and secondary homoallylic electrophiles

Article abstract of DOI:10.1021/ja305403s

The Pd(0)-catalyzed allylic cross-coupling of homoallylic tosylate substrates using boronic acids and pinacol esters is reported. The reaction uses 2-(4,5-dihydro-2-oxazolyl)quinoline (quinox) as a ligand and is performed at ambient temperature. The scope of the reaction is broad in terms of both the boronate transmetalating reagent and the substrate and includes secondary tosylates. Mechanistic studies support an alkene-mediated S_N2-type stereoinvertive oxidative addition of unactivated primary and secondary alkyl tosylates.

Full text of DOI:10.1021/ja305403s

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Communication
Palladium-Catalyzed Allylic Cross-Coupling Reactions
of Primary- and Secondary Homoallylic Electrophiles
Benjamin J. Stokes, Susanne M Opra, and Matthew S Sigman
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja305403s • Publication Date (Web): 28 Jun 2012
Downloaded from http://pubs.acs.org on June 29, 2012
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Benjamin J. Stokes, Susanne M. Opra, and Matthew S. Sigman*
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Department of Chemistry, University of Utah, 315 S. 1400 East, Salt Lake City, UT 84112, USA
Supporting Information Placeholder
onic in nature due to the weakly-coordinating tosylate counter-
ABSTRACT: The Pd(0)-catalyzed allylic cross-coupling of
ion. -Hydride elimination would then occur yielding the
diene–Pd–H complex C. Subsequent migratory alkene inser-
tion into the Pd-hydride would generate the stabilized π-allyl
intermediate D.6 Transmetallation of D followed by reductive
elimination would afford the allylic C–H functionalization
product E. This overall reaction transposes an unactivated
electrophile to formally functionalize an allylic C–H bond7 via
a Pd-migration along an alkyl chain. Herein we report the suc-
cessful development of this process, which is efficiently cata-
lyzed by a unique ligand set for Pd-catalyzed cross-couplings
of sp3 electrophiles, specifically N,N-type ligands. Equally
notably, this work also describes the first oxidative addition of
unactivated secondary tosylates to Pd(0).
homoallylic tosylate substrates using boronic acids and esters
is reported.
The reaction uses 2-(4,5-dihydro-2-
oxazolyl)quinoline (quinox) as ligand and is performed at am-
bient temperature. The scope of the reaction is broad in terms
of both the boronate transmetallating reagent and the substrate,
and includes secondary tosylates. Mechanistic studies support
an alkene-mediated SN2-type stereoinvertive oxidative addi-
tion of unactivated primary- and secondary alkyl tosylates.
Transition metal-catalyzed cross-coupling reactions are widely
recognized as among the most important class of synthetic
transformations due to the ease with which diverse coupling
partners can be combined to form specific carbon–carbon
bonds.1 While cross-coupling reactions of aryl- and vinylhal-
ides have been extensively developed over four decades, strat-
egies for the dependable cross-coupling of unactivated, -
hydrogen-containing alkyl electrophiles have been slower to
develop.2 The key mechanistic challenges in cross-couplings
of alkyl electrophiles are slow oxidative addition to the metal3
and subsequent competing -hydride elimination.4 Over the
past decade, elegant ligand-controlled strategies for the Pd-
and Ni-catalyzed cross-coupling of unactivated alkyl electro-
philes have emerged.1a,2a,2d However, harnessing the propensi-
ty for -hydride elimination from Pd-alkyl intermediates prior
to cross-coupling has not been used as a strategy for carbon–
carbon bond-formation.
Table 1. Reaction Optimizationa
% yieldb
entry
ligand
base
solvent
(2a/3a)
33 (<1:20)c
55 (>20:1)c
80 (>20:1)
70 (>20:1)
48 (>20:1)
no rxn
1
2
3
4
5
6
P(o-tol)3
P(t-Bu)3
P(t-Bu)3
quinox
pyrox
Cs2CO3
Cs2CO3
K2CO3
PhMe
PhMe
t-AmOH
t-AmOH
t-AmOH
t-AmOH
i-PrOH
Cs2CO3
Cs2CO3
Cs2CO3
KF•2H2O
Scheme 1. Proposed Mechanism of Pd(0)-Catalyzed Formal
Allylic C–H Functionalization of Homoallylic Tosylates
bpy
7
quinox
92 (>20:1)d
a
Reactions performed on 0.1 mmol scale. b Determined by GC
analysis using an internal standard and response factor correction.
c
The major byproduct was (E)-1-phenyl-1,3-butadiene. Reaction
d
carried out at 80 °C. Reaction carried out on 0.5 mmol scale
using 2.5 mol % of pre-formed Pd(quinox)Cl2 at [1] = 0.1 M.
With this in mind, we sought to establish a Pd(0)-catalyzed
reaction manifold whereby -hydride elimination would be a
mechanistic step preceding a carbon–carbon bond-forming
event.5 It was expected that homoallylic tosylates A would be
potential substrates for such a reaction (Scheme 1). Oxidative
addition of the substrate would form Pd-alkyl B, which is cati-
The reaction was optimized using homostyrenyl tosylate 1
(Table 1). The central challenge was to identify a catalytic
system capable of avoiding the formation of the Suzuki-
Miyaura product, and instead accessing the diene intermediate
through oxidative addition and rapid -hydride elimination.
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Additionally, the ligand would have to be capable of reinsert- cellent selectivity. Strongly Lewis-basic boronate nucleophiles
1
2
3
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5
6
7
8
ing the putative 1,3-diene intermediate in order to subsequent-
ly access 2a.6,8 In light of the pioneering work of Fu and
coworkers on Pd-catalyzed cross-couplings of primary alkyl
electrophiles,2a,2d our initial efforts to optimize this reaction
centered on the use of monodentate phosphine ligands (Table
1, entires 1–3). Pleasingly, the branched-to-linear selectivity of
the reaction between homostyrenyl tosylate 1 and phenyl-
boronic acid could be controlled by the choice of phosphine.
For example, tri-ortho-tolylphosphine led to the predominant
formation of the undesired cross-coupling product 3a (entry
1), while tri-tert-butylphosphine delivered the desired product
2a with excellent selectivity (entries 2 and 3). The contrasting
selectivity despite similar cone angles (182° and 194°, respec-
tively)9 prompted the evaluation of a variety of ligands.10
While we anticipated monodentate phosphines to be uniquely
suited for this reaction, we surprisingly found that quinox, a
ligand that has found utility in mechanistically distinct Wack-
er-type oxidations,11 provided 2a with the best selectivity and
yield (entries 4 and 7). Notably, the Pd(quinox)Cl2 precatalyst
is easily prepared and air stable, thus obviating the use of rig-
orous air-free techniques in our studies. The pyrox ligand re-
sulted in diminished yield (entry 5), and 2,2’-bipyridine failed
to promote the reaction (entry 6).
were not tolerated, presumably due to competitive coordina-
tion to Pd (see supporting information for details).
Table 3. Substrate Scopea
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a Isolated yields of 5a–5g are shown, with (B:L) selectivity de-
termined by 1H NMR spectroscopy of the crude reaction mixture.
b
Determined by GC analysis using an internal standard and re-
sponse factor correction. c 72 h reaction time. d An 87:13 E/Z ratio
of starting material isomers afforded a 93:7 E/Z ratio of products
as determined by 1H NMR spectroscopy. e Both yield and selectiv-
ity determined by 1H NMR spectroscopy.
Table 2. Scope of Boronate Nucleophilesa
Turning our attention to the substrate, the role of the leaving
group on the performance of the reaction was investigated
(Table 3). While homostyrenyl bromide 4a affected good yield
but slightly diminished branched selectivity compared to the
corresponding tosylate, reaction of homostyrenyl chloride 4b
resulted in only 19% yield. Next, the electronic nature of the
styrene substituent was evaluated and was found to have min-
imal effect on the reaction outcome, as both electron-donating
(4c) and electron-withdrawing (4d) functional groups were
well-tolerated in terms of both yield and selectivity. Addition-
ally, unstabilized alkenes could be used in place of styrenes, as
4e afforded the desired product in good yield and excellent
selectivity.
To evaluate the importance of the structural relationship of the
tosylate to the alkene, bis-homostyrenyl tosylate 4f was sub-
jected to the optimized conditions. This resulted in a 30:70
ratio of 5f to the linear product, as well as the recovery of the
remaining starting material. While this shows that Pd can mi-
grate to the allylic position through repeating -hydride elimi-
nation/alkene insertion steps, the low yield suggests that this
occurs inefficiently under these conditions. The fact that the
linear product is the major product in this case signifies that,
after oxidative addition, the first -hydride elimination is
slower than transmetallation. This may be due to a more facile
C–H breakage at the allylic position, a weaker C–H bond,
compared to C–H cleavage at the homoallylic site. Alterna-
tively, homoallylic substrates may be uniquely competent due
to a favorable chelation event prior to oxidative addition.12
a Isolated yields of 2b–2j are reported, with (B:L) selectivity
1
determined by H NMR spectroscopy of the crude reaction mix-
b
c
ture. Pinacol boronic ester used instead of boronic acid. 1H
NMR yield, calculated using an internal standard.
We next investigated the scope of boronate transmetallating
reagents for the functionalization of substrate 1 under the op-
timized conditions (Table 2). Aryl- and vinylboronates were
found to be generally well-tolerated. A variety of electronical-
ly-disparate para-substituted aryl boronic acids were found to
be suitable for the transformation, affording branched/linear
product ratios of ≥11:1 in each case for 2b–2e. Additionally,
meta-aminophenyl boronic acid afforded the desired product
2f in good yield with good branched product selectivity. Aryl
boronic acid pinacol esters are also suitable coupling partners
for this reaction: N-methylindole-5-boronic acid pinacol ester
delivered the branched indole product 2g exclusively and in
excellent yield, while 2h was also produced with excellent
selectivity and good yield from the corresponding pinacol
ester. Finally, E-alkenyl boronic acids could be used to access
skipped diene products 2i and 2j in good yields and with ex-
To further explore the role of the substrate in this reaction,
homobenzylic tosylate 4g (Table 3) was subjected to the reac-
tion conditions. After 16 h, the starting material was complete-
ly recovered, which supports alkene chelation to Pd prior to
oxidative addition.
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Based on this result, the following detailed mechanism is pro-
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posed to account for the formation of the major product (R)-5f
(Figure 1A). After coordination of the substrate (R)-6, stere-
oinvertive oxidative addition15a,16 to Pd(0) would generate Pd-
alkyl F, which then undergoes -hydride elimination of Hb,
affording G. Sequential alkene insertion without dissocia-
tion,17 transmetallation with Ph–B(OH)2, and stereoretentive
reductive elimination18 would afford the product. If oxidative
addition occurs with high stereochemical fidelity, it is hypoth-
esized that the -hydride elimination step must therefore be
responsible for the erosion of stereochemical integrity due to
the existence of an equilibrium between Pd-alkyl F and its
conformational isomer, F’ (Figure 1B). Conformer F features
an anti relationship between the methyl and styrenyl function-
al groups, and only Hb is positioned syn to Pd for -hydride
elimination. In contrast, conformer F’, with the methyl and
styrenyl groups oriented gauche, can eliminate either Ha or Hb.
The observed modest 40% ee favoring (R)-5f suggests similar
energetics for the selection of the two -hydrogens.
Owing to the unique behavior of primary homoallylic tosylates
detailed above, we hypothesized that secondary homoallylic
tosylates might also be amenable substrates. However, this
would require oxidative addition of Pd(0) into an unactivated
secondary tosylate.13 Pd(0)-catalyzed cross-couplings of acti-
vated alkyl electrophiles are known,14 but to the best of our
knowledge, no methods requiring Pd(0)-catalyzed oxidative
addition into unactivated secondary alkyl electrophiles have
been reported. This is generally ascribed to the high energy
barrier of the predominant SN2-type transition state proposed
by Fu and coworkers in the oxidative addition event.15 There-
fore, it is surprising that the secondary tosylate 6 was found to
convert into the corresponding allylic C–H phenylation prod-
uct 5f in moderate yield under the optimized conditions.
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It was thus envisioned that access to the problematic gauche
conformer could be minimized by increasing the steric penalty
of the gauche interaction, thereby achieving selective -
hydride elimination. To validate this hypothesis, substrate
(R)-7 was prepared via a Brown allylation and cross-
metathesis sequence.10 This substrate contains an isopropyl
group in place of the methyl group of (R)-6. Upon subjection
to identical reaction conditions, nearly complete chirality
transfer in the formation of (S)-8 was observed (92% ee, eq 3).
The absolute configuration of (S)-8 was determined by con-
verting to a previously reported compound. Based on this, the
overall stereochemical course of the reaction is strongly sug-
gestive of an SN2-type oxidative addition and conformational-
ly enforced selective -hydride elimination.
To gain insight into the stereochemical course of this reaction,
an enantiomerically-enriched variant of 6 was synthesized.
When (R)-6 was subjected to the reaction conditions, a sub-
stantial erosion in enantiomeric excess was observed: starting
from 92% ee of (R)-6, just 40% ee of (R)-5f was obtained (eq
2). The absolute configuration was determined by converting
the product into a previously reported compound of known
configuration (see supporting information for details).
Figure 1. Proposed Mechanism of Chirality Transfer Reactions
In conclusion, we have developed a general, mild, and proce-
durally simple Pd-catalyzed method for the functionalization
of allylic C–H bonds from homoallylic tosylates. The key
mechanistic features of this reaction are the stereoinvertive
oxidative addition of unactivated primary- and secondary alkyl
tosylates, and the migration of the Pd-alkyl intermediate via -
hydride elimination and migratory insertion. This reaction
employs a simple N,N-ligand in a role generally presumed to
be exclusive to monodentate phosphines. To facilitate further
reaction development, experiments are being designed to
probe the origin of this ligand-controlled process as well as the
critical role of the substrate olefin.
Supporting Information. Optimization data, experimental pro-
cedures, and characterization data. This material is available free
of charge via the Internet at http://pubs.acs.org.
* sigman@chem.utah.edu
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catalyzed Suzuki reactions, see: (a) Zultanski, S. L.; Fu, G. C. J. Am.
This work was supported by the National Institutes of Health
(R01GM063540 and F32GM099254).
Chem. Soc. 2011, 133, 15362; (b) Lu, Z.; Wilsily, A.; Fu, G. C. J. Am.
Chem. Soc. 2011, 133, 8154. For a related mechanistic study, see: (d)
Li, Z.; Jiang, Y.-Y.; Fu, Y. Chem. Eur. J. 2012, 18, 4345.
14) For recent strategies to achieve Pd(0)-catalyzed cross-coupling
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11, 5514.
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G. C. Angew. Chem., Int. Ed. 2003, 42, 5749; (c) Collman, J. P.;
Hegedus, L. S.; Norton, J. R.; Finke, R. G. In Principles and Applica-
tions of Organotransition Metal Chemistry; University Science
Books: Mill Valley, 1987, p 386.
16) Mixed modes (stereorententive and stereoinvertive) of oxida-
tive addition may contribute to the erosion in product enantiomeric
excess. For a representative examination of the intricacies of Pd-
catalyzed oxidative addition using monodentate phosphine ligands,
see: Besora, M.; Gourlaouen, C.; Yates, B.; Maseras, F. Dalton Trans.
2011, 40, 11089.
17) A crossover experiment indicates that the intermediate 1,3-
diene is not exchanged, and therefore remains bound to a single al-
kene face as required for chirality transfer. See supporting infor-
mation for details.
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2012, 134, 5738. The alkene of products such as 2 can be cleaved
under oxidative conditions to give NSAID derivatives. For a recent
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Persson, A. K. Å.; Bäckvall, J.-E. J. Org. Chem. 2010, 75, 6842.
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Asensio, G.; Maseras, F. J. Org. Chem. 2009, 74, 4049.
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secondary alkyl halides, see references 2b and 2c. For recent Ni-
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