Operationally simple and highly (E)-styrenyl-selective heck reactions of electronically nonbiased olefins

Article abstract of DOI:10.1021/ja203164p

Simple, mild, and efficient conditions are reported for a Pd ⁰-catalyzed Heck reaction that delivers high yields and selectivity for (E)-styrenyl products using electronically nonbiased olefin substrates bearing a range of useful functionality. Preliminary mechanistic studies demonstrate that the σ-donating DMA solvent is crucial for high selectivity. Further studies suggest that the catalyst distinguishes between β-hydrogens on the basis of their relative hydridic character, in contrast to previously reported Pd^II-catalyzed oxidative reaction conditions.

Full text of DOI:10.1021/ja203164p

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pubs.acs.org/JACS
Operationally Simple and Highly (E)-Styrenyl-Selective Heck Reactions
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, United States
S Supporting Information
b
partial radical character, has engaged our interest in this
fundamental organometallic process.
ABSTRACT: Simple, mild, and efficient conditions are
reported for a Pd0-catalyzed Heck reaction that delivers high
yields and selectivity for (E)-styrenyl products using elec-
tronically nonbiased olefin substrates bearing a range of
useful functionality. Preliminary mechanistic studies de-
monstrate that the σ-donating DMA solvent is crucial for
high selectivity. Further studies suggest that the catalyst
distinguishes between β-hydrogens on the basis of their
relative hydridic character, in contrast to previously reported
PdII-catalyzed oxidative reaction conditions.
While the aforementioned report significantly improved the
substrate scope of the oxidative Heck reaction, the reaction
requires catalyst synthesis, a 3-fold excess of the arene organo-
metallic, and a catalytic amount of copper salts to proceed with
high yield and excellent selectivity. Additionally, these conditions
are incompatible with some common functional groups, such as
carboxylic acids and nitriles. Guided by our previous mechanistic
studies, we report herein the development of a complementary
and operationally simple Pd0-catalyzed Heck reaction using
electronically unbiased terminal alkenes, which allows for the
introduction of diverse functional groups and is highly selective
for (E)-styrenyl products.
In order to achieve high selectivity, it was hypothesized that
mimicking the electrophilic nature of the proposed PdII-σ-alkyl
intermediate A capable of distinguishing between β-hydrogens
would be essential, and that the elevated temperatures typically
required for oxidative addition should be avoided. As such, it was
envisioned that aryldiazonium tetrafluoroborates, pioneered by
Matsuda, would be well-suited as the oxidant in light of both their
tendency to undergo facile oxidative addition5 and the non-
coordinating nature of the BF4 counterion of the resultant aryl-
PdII complex.6 An initial experiment utilizing this oxidant
resulted in a modest yield and relatively low selectivity
(Table 1, entry 1).7
he Heck reaction, or palladium-catalyzed substitution of a
T
vinylic CÀH bond for an arene, is a transformation uti-
lized extensively in synthesis despite significant limitations.1
Arguably, the most restrictive limitation is the required use
of an electronically biased olefin, such as a styrene or an
R,β-unsaturated carbonyl, in order to deliver a single arylated
alkene isomer. In the absence of substrate bias, a mixture
of olefin products arises under both typical Pd0-catalyzed
and most oxidative PdII-catalyzed2 Heck reaction conditions.
This mixture of products likely results from PdII-σ-alkyl
intermediate A undergoing indiscriminate β-hydride elimina-
tion with either HS or HA (eq 1).3 Additionally, there exists
no generally applicable set of Heck conditions; param-
eters typically must be optimized for a specific desired
reaction.1b
A control experiment (entry 2) excluding the N-heterocyclic
carbene ligand delivered higher selectivity, prompting the elim-
ination of this additive in future experiments. A significant
disparity between consumption of substrate and product yield
dictated the careful monitoring of this ratio over time, revealing
reaction completion after only 15 min and further consumption
of the product if the reaction mixture is not quenched (entry 2 vs 3).8
Decreased catalyst and arene loadings resulted in improved yield and
selectivity (entries 4 and 5), while entry 6 confirms that palladium is
required. Of particular note, the use of MeOH or MeCN, solvents
commonly employed in MatsudaÀHeck reactions,5 results in very
poor selectivity (entries 7 and 8).
Recently, we reported a PdII-catalyzed oxidative Heck reaction
capable of delivering a variety of (E)-styrenyl products from
electronically nonbiased terminal alkene substrates, where the
high selectivity observed was attributed to catalyst control
(eq 2).4 Specifically, preliminary mechanistic studies sug-
gested that the unusually high selectivity resulted from a
cationic palladium catalyst stabilized by a strongly σ-donating
ligand. It appears that, when undergoing β-hydride elimina-
tion from A, this metal center is capable of distinguishing
between HA and HS on the basis of relative CÀH bond
strength. This surprising result, which suggests that the
hydrogen leaving in the selectivity-determining step may have
Received: April 6, 2011
Published: May 31, 2011
r
2011 American Chemical Society
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Table 1. Optimization of the Heck Reaction
Table 2. Scope of the Heck Reaction
entry
x
y
time
16 h
conversion,a %
yield,a %
selectivityb
1c
2
5
5
5
3
3
0
3
3
1.5
1.5
1.5
1.5
1.1
1.1
1.1
1.1
>99
>99
>99
>99
>99
3.6
68.4
43.3
62.6
86.2
>99
0
3.8
6.8
16 h
15 min
15 min
15 min
15 min
15 min
15 min
3
7.1
4
7.5
5
10.7
À
6
7d
8e
>99
20
0.2:1
98.1
15
0.3:1
a Conversion and yield were calculated by comparing starting material
and product peak integration to integration of internal standard using
corrected GC analysis. Yield refers to the sum of all product isomers.
b Selectivity refers to the ratio of (E)-styrene to all other isomers. c 12.5
i
mol % Pr carbene added. d MeOH used as solvent e MeCN used as
solvent.
The optimized conditions were evaluated for compatibility
with a variety of substrates that performed well under oxidative
conditions.4 For example, substrates bearing an ester (Table 2,
entry 1), a ketone (entry 2), and a silyl ether (entry 3) all proceed
with excellent yield and selectivity. A free homoallylic alcohol
(entry 4) was compatible, and, more surprisingly, an allylic
acetate is an excellent substrate that does not undergo oxidative
addition under these conditions (entry 5).9 A doubly protected
allylic amine is a good substrate,10 as is a distal free alcohol
(entries 6 and 7). The PdII-catalyzed conditions are incompatible
with carboxylic acids,4 but gratifyingly, 3h and 3i were pre-
pared in good to excellent yield using the present system
(entries 8 and 9). Of note, the heteroatom-free substrate
dodecene gives excellent results, providing strong evidence
that the selectivity observed under these conditions is catalyst-
controlled rather than dependent on substrate chelation
(entry 10).11 A substrate bearing a nitrile (also incompatible
with oxidative conditions) is arylated with either a phenyl
group or an arene bearing a methyl ester (entries 11 and 12). A
free 1,2-diol reacts cleanly when installing a phenyl group, but
the yield suffers when installing an arene with more steric bulk
(cf. entries 13 and 14). Free phenols and aryl chlorides are
compatible with these conditions (entries 15 and 16), and
submission of a free allylic alcohol gives the desired product,
but the reaction proceeds more slowly and the yield is
diminished due to the formation of a ketone byproduct
(entry 17).12 Challenging nitro- and iodo-substituted arenes
are also compatible under the conditions described, providing
valuable handles for further functionalization (entries 18 and
19).13 The reaction proceeds rapidly and in high yield using R-
methylstyrene as the substrate, but unfortunately a mixture of
olefin isomers is observed (entries 20 and 21).14 Finally, a
highly enantiomerically enriched substrate that may be sus-
ceptible to racemization suffers no erosion of enantiomeric
excess (entry 22).
a Yields are averages of two experiments performed on a 0.5 mmol scale
and are the sum of all product isomers. The selectivity for (E)-styrene
was >20:1 unless otherwise noted. b Selectivity for (E)-styrene was 10:1.
c Using 5 mol % Pd2dba3 and 1.5 equiv of ArN2BF4. d Isolated 44%
ketone product. e Obtained ∼1:1 mixture of olefin isomers.
that the selectivity of a reaction performed on larger scale may
suffer. Therefore, on 5 mmol scale, 1a was subjected to the
conditions described to prepare 3a, except that the catalyst load-
ing was decreased to 2 mol % and the reaction was performed at
À15 °C (eq 3). Under these conditions, 3a was obtained in
While evaluating the scope of this transformation, it was
observed that the reaction is highly exothermic, raising concerns
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relationship observed suggests that the origin of selectivity under
these conditions is related to the ability of the metal center in
intermediate X to distinguish between β-hydrogens as a function of
their relative hydridic nature.16,17 Therefore, submission of electron-
rich diazonium salts results in relatively more 5Ar, due to the greater
ability of the newly installed arene to stabilize partial positive charge
developing during β-hydride elimination. Consistent with this
proposal, submission of electron-deficient aryldiazonium salts re-
sults in relatively more 5Ph, due to destabilization of partial positive
charge by the newly installed arene. These results contrast markedly
with those observed under oxidative PdII catalysis,4 suggesting an
interesting mechanistic complementarity along with the more
intuitive counterpart arising from the differing oxidation states of
the two precatalysts.
In conclusion, we have developed simple and efficient condi-
tions for a Pd0-catalyzed Heck reaction that delivers high selectivity
for (E)-styrenyl products in the absence of substrate bias. This
reaction is compatible with a greater range of functional groups than
the related PdII system and utilizes a commercially available catalyst.
Additionally, the reaction requires no base, no elevated temperatures,
nor additional oxidant. For most substrates evaluated, the reaction is
completed rapidly, but the rate is retarded when using substrates with
allylic coordinating groups. Some functional groups are incom-
patible,10 but it is reasonably easy to predict these, providing another
advantage over other Heck protocols, which can require optimization
for each substrate. Initial mechanistic experiments suggest that the
selectivity observed is highly sensitive to the identity of the solvent. A
linear free energy relationship probing product distribution as a
function of the electronic nature of the introduced arene suggests that
this catalyst selects between β-hydrogens on the basis of their
hydridic nature, in contrast with the PdII system previously reported.
This reactivity manifold has inspired further experiments designed to
probe the factors that dictate selectivity in β-hydride elimination from
related organometallic intermediates. Investigations in this pursuit are
currently underway in our laboratory.
Table 3. Product Distribution Using a β,γ-Unsaturated Ester
Ar
4-H
5Sty/5Allyl
Ar
5Sty/5Allyl
6.03
6.11
7.87
4-CO2Me
4-Br
7.69
6.47
6.12
4-NO2
4-OMe
4-F
’ ASSOCIATED CONTENT
S
Supporting Information. Optimization data, experimen-
b
tal procedures, and characterization data. This material is avail-
Figure 1. Hammett plot.
able free of charge via the Internet at http://pubs.acs.org.
comparable yield and improved selectivity for the (E)-styrenyl
product after 5.5 h.
’ AUTHOR INFORMATION
Corresponding Author
sigman@chem.utah.edu
Having established that the active catalyst described in this
report indeed exhibits a unique preference for (E)-styrenyl products,
we wished to gain an understanding of how, exactly, the catalyst
imparts selectivity. The mechanistic origin of selectivity under
oxidative conditions was previously determined by submitting
β,γ-unsaturated ester 1t to PdII-catalyzed conditions using a variety
of electronically disparate arene sources—an experiment designed
to probe the selectivity-determining β-hydride elimination step
where a significant substituent effect was observed.4 Interestingly,
the product distribution measured under Pd0-catalyzed conditions
reveals no clear trend, with styrene products favored in similar ratios
regardless of the electronic nature of the arene (Table 3).15
A more sensitive mechanistic experiment was designed, where-
by allyl benzene was submitted to the optimal conditions with a
variety of electronically disparate aryldiazonium salts. In this pro-
duct-partitioning experiment, the catalyst must distinguish between
two benzylic hydrogens, which presumably differ only by virtue of
the arenes immediately adjacent (Figure 1). The linear free energy
’ 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.
’ REFERENCES
(1) For reviews of the Heck reaction see the following. (a) Information
regarding substrate scope: Heck, R. F. Org. React. 1982, 27, 345–390. (b)
Updated scope information and brief mechanistic discussion: Meijere, A.;
Meyer, F. E. Angew. Chem., Int. Ed. 1994, 33, 2379–2411. (c) Mechanistic
details: Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100,
3009–3066. (d) Advances using aryl chloride and aryl bromide oxidants:
Whitcombe, N. J.;Hii, K. K.;Gibson, S. E.Tetrahedron 2001, 57, 7449–7476.
(e) Use of 1,1-disubstituted olefins as substrates: Kondolff, I.; Doucet, H.;
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Santelli, M. Tetrahedron Lett. 2003, 44, 8487–8491. (f) Advances in
asymmetric Heck methodology: Dounay, A. B.; Overman, L. E. Chem.
Rev. 2003, 103, 2945–2964.
synthetically inaccessible aryldiazonium salts. See Supporting Informa-
tion for details.
(14) See Supporting Information for details.
(2) For examples of the oxidative Heck reaction, see: (a) 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. (b) Parrish, J. P.; Jung, Y. C.; Shin, S. I.; Jung, K. W. J. Org.
Chem. 2002, 67, 7127–7130. (c)Jung, Y. C.;Mishra, R. K.;Yoon, C. H.;Jung,
K. W. Org. Lett. 2003, 5, 2231–2234. (d) Andappan, M. M. S.; Nilsson, P.;
von Schenck, H.; Larhed, M. J. J. Org. Chem. 2004, 69, 5212–5218. (e) Yoo,
K. S.; Yoon, C. H.;Jung, K. W. J. Am. Chem. Soc. 2006, 128, 16384–16393. (f)
Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y. Science 2000,
287, 1992–1995. (g) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009,
131, 5072–5074. (h) 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.
(15) Interestingly, allylic products 5Allyl were typically favored under
oxidative Heck conditions, while they were the minor products under
these conditions regardless of arene. See Supporting Information for
details.
(16) For examplesofHammettanalysesofotherHeckreactions, 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, 6160–6165.
(17) The modest slope of the Hammett plot may explain why no
trend was apparent when attempting to construct a similar Hammett
plot using a β,γ-unsaturated ester as the substrate. It is likely that the
hydridic nature of benzylic hydrogens is significantly different from that
of hydrogens R to an ester.
(3) Additional byproducts can arise from Heck insertion in the
opposite orientation resulting in terminal olefin products, and internal
olefin isomeric products arising from PdÀH migration. (Z)-Olefin
isomers may also be observed.
(4) Werner, E. W.; Sigman, M. S. J. Am. Chem. Soc. 2010,
132, 13981–13983.
(5) For seminal work, see: (a) Kikukawa, K.; Nagira, K.; Wada, F.;
Matsuda, T. Tetrahedron 1981, 37, 31–36. For reviews of the use of
aryldiazonium salts in Pd-catalyzed cross-coupling reactions, see: (b) Roglans,
A.; Pla-Quintana, A.; Moreno-Manas, M. Chem. Rev. 2006, 106, 4622–4643.
(c) Taylor, J. G.; Moro, A. V.; Correia, C. R. D. Eur. J. Org. Chem.
2011, 1403–1428. For a mechanistic study of the MatsudaÀHeck
reaction, see: (d) Sabino, A. A.; Machado, A. H. L.; Correia, C. R. D.; Eberlin,
M. N. Angew. Chem., Int. Ed. 2004, 43, 2514–2518. For a recent example
utilizing in situ-prepared aryldiazonium salts, see: (e) Callonnec, F. L.;
Fouquet, E.; Felpin, F.-X. Org. Lett. 2011, 13, 2646–2649.
(6) The pKa of the conjugate acid provides a commonly used
estimation of the coordinative abilities of counterions in catalysis; the
pKa of HBF4 is À5.
(7) Throughout the paper, when isomers are detected they arise
either from migratory insertion in the opposite direction to give terminal
olefin products or from olefin migration via nonselective β-hydride
elimination. (Z)-Olefin isomers were not observed.
(8) A minor byproduct arises from a subsequent Heck reaction of
the resultant styrene utilizing the remainder of the aryldiazonium salt.
The desired product is also believed to be oligomerized in the reaction
mixture overtime, likely due to the equivalent of HBF4 generated in the
reaction. See Supporting Information for details.
(9) Allylic acetates are known to be displaced by Pd0 to form π-allyl
complexes. For a review, see: Trost, B. M Angew. Chem., Int. Ed. 1989,
28, 1173.
(10) More basic nitrogen functionality, such as a trialkyl amine-
containing substrate, was incompatible with these conditions. Other
incompatible functionality included quinoline and indole arenes. See
Supporting Information for further details.
(11) For examples of chelation-controlled Heck reactions, see: (a)
Filippini, L.; Gusmeroli, M.; Riva, R. Tetrahedron Lett. 1993,
34, 1643–1646. (b) Kang, S. K.; Lee, H. W.; Jang, S. B.; Kim, T. H.;
Pyun, S. J. J. Org. Chem. 1996, 61, 2604–2605. (c) Olofsson, K.; Sahlin,
H.; Larhead, M.; Hallberg, A. J. Org. Chem. 2001, 66, 544–549. (d)
Buezo, N. D.; Rosa, J. C.; Priego, J.; Alonso, I.; Carretoero, J. C. Chem.
Eur. J. 2001, 7, 3890–3900. (e) Delcamp, J. H.; Brucks, A. P.; White,
M. C. J. Am. Chem. Soc. 2008, 130, 11270–11271.
(12) Ketones like 6 are usually the major product observed using free
allylic alcohols under Heck conditions; see above references.
(13) It is important to note that, while most aryldiazonium salts
submitted to this reaction performed well, there are several examples of
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