A highly selective and general palladium catalyst for the oxidative heck reaction of electronically nonbiased olefins

Article abstract of DOI:10.1021/ja1060998

A general, highly selective oxidative Heck reaction is reported. The reaction is high-yielding under mild conditions without the need for base or high temperatures, and the selectivity is excellent, without the requirement for electronically biased olefins or other specific directing groups. A preliminary mechanistic investigation suggests that the unusually high selectivity may be due to the catalyst's sensitivity to C-H bond strength in the selectivity-determining β-hydride elimination step.

Full text of DOI:10.1021/ja1060998

Published on Web 09/21/2010
A Highly Selective and General Palladium Catalyst for the Oxidative Heck
Reaction of Electronically Nonbiased Olefins
Erik W. Werner and Matthew S. Sigman*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East, Salt Lake City, Utah 84112
Received July 9, 2010; E-mail: sigman@chem.utah.edu
Table 1. Optimization of the Oxidative Heck Reaction
Abstract: A general, highly selective oxidative Heck reaction is
reported. The reaction is high-yielding under mild conditions
without the need for base or high temperatures, and the selectivity
is excellent, without the requirement for electronically biased
olefins or other specific directing groups. A preliminary mecha-
nistic investigation suggests that the unusually high selectivity
may be due to the catalyst’s sensitivity to C-H bond strength in
the selectivity-determining ꢀ-hydride elimination step.
entry
additive
temperature
x
% conversiona
% yielda
1
2
3
3 Å MS
3 Å MS
rt
25
25
25
20
20
0
22
>99
98
19
85
93
>99
<1
12
5
40 °C
40 °C
40 °C
40 °C
40 °C
40 °C
-
-
-
-
-
4
>99
The oxidative Heck reaction, a transformation in which a vinylic
C-H bond is converted to a C-C bond under PdII catalysis, has the
potential for broad synthetic applications.1,2 Unfortunately, most
examples require the use of an electronically biased olefin such as an
acrylate to deliver high selectivity for the (E)-styrenyl product. A
notable exception recently reported by White and co-workers3 is
proposed to rely on substrate chelation to afford these products as the
only observable isomer. The poor selectivity under typical Heck
conditions presumably arises from the metal center’s lack of ability to
distinguish between HS or HA when undergoing ꢀ-hydride elimination
(eq 1), resulting in a mixture of often-inseparable styrenyl and allylic
products.4 Herein, we report a highly selective and general oxidative
Heck reaction with a unique preference for the (E)-styrenyl products
governed by catalyst control. Additionally, this reaction does not require
base and is efficient at mild temperatures.
5b
6
<1
64
7c
20
5
a Conversion and yield were calculated by comparing starting
material and product peak integrations to the integration for an internal
standard using GC analysis. b No Pd(IiPr)(OTs)2 was used. c The
reaction was run under nitrogen.
Optimization of this reaction was performed, and it was found
that raising the temperature to 40 °C improved the yield without
diminishing the selectivity. Removing molecular sieves (MS) and
decreasing the Cu(OTf)2 loading further improved the GC yield to
>99% with >20:1 selectivity for the (E)-styrenyl isomer (Table 1).
Finally, performing the reaction in the absence of the PdII catalyst,
Cu(OTf)2, or O2 resulted in little to no reactivity (entries 5-7).
Submission of substrate 1a, which is susceptible to ꢀ-acetoxy
elimination, to the optimized reaction conditions on a 0.5 mmol
scale resulted in a 95% yield of the desired product (Table 2, entry
1).6
In view of the unusually high selectivity observed, we chose to
examine the scope of this transformation. The reaction proved to
be tolerant of a wide variety of functional groups commonly
encountered in organic synthesis, delivering the desired (E)-styrenyl
product in a >20:1 ratio in most cases. Electron-deficient arylboronic
esters were highly effective (Table 2, entries 2 and 3). A substrate
containing a TBS-protected homoallylic alcohol gave good yields
and high selectivity for a range of arylboronic esters (entries 4-7).
A free homoallylic alcohol was also a compatible substrate,
delivering the desired product in moderate yield (entry 8). Other
functional groups on simple alkenes were well-tolerated, including
a distal free alcohol (entry 9), a primary chloride (entry 10), a ketone
(entry 11), and an ester (entry 12). Use of a hindered arylboronic
ester required increased catalyst loading and elevated temperatures,
resulting in a reduction in selectivity (10:1 olefin isomer ratio; entry
13). An acetonide-protected diol was an excellent substrate even
though a Lewis acidic catalyst was used (entry 14). Nitrogen-
containing substrates are incompatible with previously reported
reactions utilizing this catalyst, but an allylic amine with two
carbamate protecting groups (entry 15) performed well in the present
reaction. However, a more electron-rich carbamate led to poor
catalyst activity (entry 16). Finally, a substrate containing a
trisubstituted olefin (entry 17), which may preferentially bind to
but not react with the catalyst, was a poor substrate under these
We recently reported an olefin diarylation reaction that utilizes
the oxidative Heck mechanistic manifold but intercepts reactive
PdII-alkyl intermediates with an arylstannane in a second trans-
metalation event (eq 2).5 The success of this system was partially
attributed to the cationic nature of the catalyst. In view of the
ubiquitous nature of arylboronic acid derivatives in cross-coupling,
we chose to evaluate these in our alkene difunctionalization
reactions. To our surprise, the use of phenylboronic ester 4a in
place of PhSnBu3 afforded only the (E)-styrenyl Heck product 5a
with no observed diarylation or isomeric products (eq 3).
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10.1021/ja1060998  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 13981–13983 13981

C O M M U N I C A T I O N S
Table 2. Scope of the Oxidative Heck Reaction
Table 3. Common PdII Salts in the Oxidative Heck Reaction
entry
PdII source
CuII source
% conversiona % yielda selectivityb
1
2
3
4
5
6
Pd(MeCN)2Cl2
Pd(OAc)2
Pd(OAc)2
CuCl2
Cu(OAc)2
Cu(OTf)2
15.3
>1
-
>99
35.3
55.7
99
6.2:1
>99
>99
2.0:1
3.4:1
4.4:1
9.8:1
Pd(MeCN)2(OTs)2 Cu(OTf)2
[Pd(IiPr)Cl2]2
Pd(IiPr)(OTs)2
Cu(OTf)2
Cu(OTf)2
79.6
60.8
96.3
>99
a Conversion and yield were calculated by comparing starting
material and product peak integrations to the integration for an internal
standard using GC analysis. Each reported yield is the sum for all of the
isomers. b The selectivity is 5r:(all other isomers), as determined by GC
analysis.
In order to demonstrate that the high selectivity observed under
these conditions is attributable to the Pd(IiPr)(OTs)2 catalyst, we
submitted substrate 1l, which is highly susceptible to the formation
of undesired isomeric products, to similar conditions using more
traditional catalysts (Table 3).7 The reaction did not proceed when
chloride was used as the counterion on palladium and copper (entry
1), whereas the acetate anion was more effective, delivering the
product in diminished selectivity in comparison with our system
(entry 2 vs 6). Using Pd(OAc)2 or Pd(MeCN)2(OTs)2 in conjunction
with Cu(OTf)2 resulted in the precipitation of Pd(0) (entries 3 and
4), and while the [Pd(IiPr)Cl2]2 catalyst did not decompose in the
presence of Cu(OTf)2, the reaction proceeded more sluggishly (entry
5 vs 6). These results suggest that both a highly electrophilic
palladium and the stabilizing ligand are crucial for selective and
high-yielding catalysis.
In view of the unusually high selectivity observed in this
oxidative Heck reaction, we wished to gain insight into the
mechanistic origin of the selectivity. Specifically, we wished to
probe whether the hydrogen atom undergoing ꢀ-hydride elimination
in the selectivity-determining step displayed protic, hydridic, or
hydrogen-atom-like character. To accomplish this, ꢀ,γ-unsaturated
ester 1l was subjected to the reaction conditions with electronically
disparate arylboronic esters. This experiment probed the partitioning
of intermediate X via ꢀ-hydride elimination of either HA or HS
(Figure 1). Plotting the logarithm of the ratio of products 5A and
5S versus the Hammett σ value for the arylboronic ester substituent
resulted in an unusual Hammett correlation wherein a break in
linearity at σ ) 0 (R ) H) was revealed.8,9
Typically, a Hammett correlation of this type is attributed to a
change in reaction mechanism. In this case, electron-rich arenes
favor the styrenyl product in comparison with phenyl, wherein the
electron donor on the arene supports a buildup of positive charge
that results in a classic hydridic delivery of HS to Pd. Surprisingly,
electron-poor arenes also favor the styrenyl product relative to
phenyl. On the basis of a change-in-mechanism analysis, a possible
explanation is that electron-poor substituents stabilize a developing
negative charge at the benzylic site, implying that the loss of HS is
more protic in nature. However, if acidity dominates the product
ratio, one would expect to observe the R,ꢀ-unsaturated ester as the
overwhelming product, since the pKa of protons R to an ester is
substantially lower than that of toluene.10 Another interesting
possibility is that the strength of the C-H bond dictates the product
distribution in this reaction. Indeed, both electron-donating and
electron-withdrawing substituents have been reported to stabilize
radicals on toluene derivatives relative to toluene itself.11 While
this analysis is clearly in the preliminary stages, the electrophilic
a Yields are averages of two experiments performed on a 0.5 mmol
scale. The selectivity for (E)-styrene was >20:1 unless otherwise noted.
c
b Selectivity for (E)-styrene was 10:1. Using 10 mol % Pd(IiPr)(OTs)2.
d Recovered 44% starting material. e Selectivity for (E)-styrene was 6:1.
f The remainder of the mass balance for this reaction was mainly
recovered starting material
conditions, giving a yield of only 30%. Notably, an enantiomerically
enriched substrate was subjected to the reaction conditions (eq 4)
with no erosion in enantiomeric excess, further demonstrating this
reaction’s potential utility in organic synthesis.
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13982 J. AM. CHEM. SOC. VOL. 132, NO. 40, 2010

C O M M U N I C A T I O N S
Acknowledgment. This work was supported by the National
Institutes of Health (NIGMS RO1 GM3540). We are grateful to
Johnson Matthey for the gift of various Pd salts.
Supporting Information Available: Optimization data, experimen-
tal procedures, and characterization data. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(1) For reviews of the Heck reaction, see: (a) Heck, R. F. Org. React. 1982,
27, 345–390. (b) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000,
100, 3009–3066. (c) Whitcombe, N. J.; Hii, K. K.; Gibson, S. E.
Tetrahedron 2001, 57, 7449–7476. (d) Kondolff, I.; Doucet, H.; Santelli,
M. Tetrahedron Lett. 2003, 44, 8587–8491.
(2) For examples of the oxidative Heck reaction, see: (a) Jia, C.; Piao, D.;
Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y. Science 2000, 287, 1992–
1995. (b) Du, X.; Suguro, M.; Hirabayashi, K.; Mori, A.; Nishikata, T.;
Hagiwara, N.; Kawata, T.; Okeda, T.; Wang, H. F.; Fugami, K.; Kosugi,
M. Org. Lett. 2001, 3, 3313–3316. (c) Parrish, J. P.; Jung, Y. C.; Shin,
S. I.; Jung, K. W. J. Org. Chem. 2002, 67, 7127–7130. (d) Jung, Y. C.;
Mishra, R. K.; Yoon, C. H.; Jung, K. W. Org. Lett. 2003, 5, 2231–2234.
(e) Andappan, M. M. S.; Nilsson, P.; von Schenck, H.; Larhed, M. J. J.
Org. Chem. 2004, 69, 5212–5218. (f) Yoo, K. S.; Yoon, C. H.; Jung, K. W.
J. Am. Chem. Soc. 2006, 128, 16384–16393. (g) Jia, C.; Piao, D.; Oyamada,
J.; Lu, W.; Kitamura, T.; Fujiwara, Y. Science 2000, 287, 1992–1995. (h)
Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 5072–
5074. (i) Zhang, X.; Fan, S.; He, C.-Y.; Wan, X.; Min, Q.-Q.; Yang, J.;
Jiang, Z.-X. J. Am. Chem. Soc. 2010, 132, 4506–4507.
Figure 1. Hammett plot.
nature of the catalyst coupled with the exceptional observed
selectivity for benzylic C-H bond abstraction is highly suggestive
of this hypothesis.
(3) Delcamp, J. H.; Brucks, A. P.; White, C. M. J. Am. Chem. Soc. 2008, 130,
11270–11271.
(4) Additional byproducts can arise from Heck insertion in the opposite
orientation, resulting in terminal olefin products and internal olefin isomeric
products arising from Pd-H migration. (Z)-Olefin isomers may also be
observed.
(5) (a) Werner, E. W.; Urkalan, K. B.; Sigman, M. S. Org. Lett. 2010, 12,
2848–2851. (b) Urkalan, K. B.; Sigman, M. S. Angew. Chem., Int. Ed.
2009, 48, 3146–3149.
(6) Submission of the corresponding allylic chloride resulted in no reaction.
(7) Use of substrate 1l under the chelation-controlled conditions reported in
ref 3 resulted in a 1.2:1 mixture, as determined by 1H NMR integration.
(8) For examples of Hammett analyses of other Heck reactions, see: (a)
Benhaddou, R.; Czernecki, S.; Ville, G.; Zegar, A. Organometallics 1988,
7, 2435–2439. (b) Fristrup, P.; Le Quement, S.; Tanner, D.; Norrby, P. O.
Organometallics 2004, 23, 6160.
(9) As a control experiment, a mixture of 5A and 5S was submitted to a separate
oxidative Heck reaction to form 5e wherein no change in the ratio was
observed.
In conclusion, we have reported the first oxidative Heck reaction
to deliver high selectivity for (E)-styrenyl products without the
requirement that particular functionality be present in the substrate.
This reaction is generally high-yielding and tolerant of diverse
functionality and performs well under mild reaction conditions with
no need for base or high temperatures. The nature of ꢀ-hydride
elimination in the selectivity-determining step was probed through
product partitioning analysis. Two linear free-energy relationships,
depending on the electronic nature of the boronic ester, were
obtained from these studies, suggesting that the selectivity may be
governed by the C-H bond strength. Given the unexpected nature
of this result, we plan to study the mechanism of this transformation
and determine the factors that result in high selectivity for styrenyl
products. These investigations are currently underway in our
laboratory.
(10) Protons R to esters have a pKa values of ∼25, while the pKa of toluene is
38.
(11) Wu, Y.-D.; Wong, C.-L.; Chan, K. W. K. J. Org. Chem. 1996, 61, 746–750.
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