Palladium-catalyzed 1,1-difunctionalization of ethylene

Article abstract of DOI:10.1021/ja304344h

The 1,1-difunctionalization of ethylene, with aryl/vinyl/heteroaryl transmetalating agents and vinyl electrophiles, is reported. The reaction is high-yielding under a low pressure of ethylene, and regioselectivity is generally high for the 1,1-disubstituted product. The process is highlighted by the use of heteroaromatic cross-coupling reagents, which have not been competent reaction partners in previously reported efforts.

Full text of DOI:10.1021/ja304344h

Communication
pubs.acs.org/JACS
Palladium-Catalyzed 1,1-Difunctionalization of Ethylene
Vaneet Saini and Matthew S. Sigman*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-0085, United States
S
* Supporting Information
Scheme 1. Proposed 1,1-Difunctionalization of Ethylene
with Vinyl Electrophiles and Boronic Acids
ABSTRACT: The 1,1-difunctionalization of ethylene,
with aryl/vinyl/heteroaryl transmetalating agents and
vinyl electrophiles, is reported. The reaction is high-
yielding under a low pressure of ethylene, and
regioselectivity is generally high for the 1,1-disubstituted
product. The process is highlighted by the use of
heteroaromatic cross-coupling reagents, which have not
been competent reaction partners in previously reported
efforts.
thylene is an industrial petrochemical and natural product
E
with an annual production of >100 million tons.
Additionally, up to 30% of all petroleum-based commodity
chemicals are derived from ethylene, as suggested by it being
the most abundant organic chemical produced globally by
volume.1 However, the utility and abundance of ethylene has
not found frequent use in fine chemical and complex target
synthesis, although notable exceptions include Heck reactions,2
alkene hydrovinylation reactions pioneered by Rajanbabu,3 and
enyne metathesis processes.4 Besides the general technical
complexities of using a gas, the potential reason for the scarcity
of reports exploiting ethylene for synthesis may arise from its
inherent simplicity. That is, addition of one functional group to
the ethylene framework (e.g., the Wacker oxidation5 or a Heck
reaction2) results in molecules of modestly enhanced complex-
ity. Therefore, we sought to develop new complexity-generating
cross-coupling reactions involving ethylene. In this regard, we
report herein a mild, three-component coupling of vinyl
electrophiles, a diverse array of organometallic reagents,
including heteroaromatic partners, and 15 psi pressure of
ethylene to construct two C−C bonds at a terminal end of
ethylene.
intermediate C, which is likely promoted by the formation of a
π-allyl adduct D. Subsequent cross-coupling of a boronic acid
with D completes the proposed catalytic cycle, furnishing the
1,1-ethylene difunctionalization product. It should be noted
that reductive elimination8 can occur on either side of the π-
allyl intermediate; as a consequence of this, the other
regioisomer can be observed. Nevertheless, the regioselectivity
is likely biased by the formation of the thermodynamically more
favorable endocyclic double bond.
Ethylene was subjected to slightly modified optimal
conditions previously reported by our group for the
difunctionalization of terminal olefins (Table 1, entry 1).6a
Only a modest yield of the desired product was observed at 15
psi of ethylene, and conversion of the vinyl triflate 1a, which is
the limiting reagent in this reaction, was incomplete. Increasing
the pressure of ethylene to 30 psi did not improve the outcome
(entry 2). To improve the conversion of the vinyl triflate,
electron-rich phosphines were evaluated and, not surprisingly, a
significant amount of the Suzuki product was observed
consistent with faster transmetalation than ethylene insertion.
More Suzuki product was observed as a function of the
phosphine cone angle (entries 3−5).9 Considering the
ineffectiveness of phosphines as well as solvent variation for
improving yields (see Supporting Information), other ligands
were considered. Specifically, dibenzylidineacetone (dba) was
evaluated, as it was reasoned that this ligand would help
stabilize Pd(0) intermediates from decomposition, but may not
For the past several years, our group has been focused on the
development of palladium-catalyzed alkene difunctionalization
reactions that avoid Heck products resulting from β-hydride
elimination.6 Conceptually, most of these reactions rely on the
formation of stabilized Pd-alkyl intermediates. In the case of
ethylene difunctionalization, we propose the use of a cyclic
vinyl triflate, similar to our recently reported three-component
coupling reaction of simple terminal alkenes,6a to initiate the
catalysis. This is due to the relative ease with which these
reagents undergo oxidative addition to form intermediates of
type A (Scheme 1). Additionally, the resultant Pd(II)-complex
is electrophilic in nature due to the noncoordinating counter-
ion, which should facilitate ethylene insertion to avoid the
Suzuki cross-coupling pathway.7 The most intriguing mecha-
nistic step is the Pd migration via β-hydride elimination of the
Pd−alkyl B and reinsertion of the diene into the putative Pd−H
Received: May 4, 2012
Published: July 5, 2012
© 2012 American Chemical Society
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Communication
nonaflates and triflates were used interchangeably throughout
these studies. Heterocyclic triflates containing oxygen (3j−3l)
and Boc-protected nitrogen groups (3m−3q) performed well,
although modest effects on regioselectivity were observed. As
previously observed, linear vinyl triflates are effective coupling
partners but a significant reduction in the ratio of 3 to 4 is
observed.6a
Functionalized phenyl boronic acids with electron-donating
substituents such as methoxy and isopropoxy at the para
position are excellent coupling partners with high regioselec-
tivity observed (3c, 3d). Various phenyl boronic acids bearing
common functional groups in synthesis are good substrates: an
aldehyde (3e, 3k, 3q), an ester (3f), a ketone (3g, 3m), and a
chloride (3l). Tertiary (3r), secondary (3h), and free amides
(3i) were found to be compatible functional groups under these
reaction conditions. Electron-withdrawing substrates, such as 4-
trifluoromethyl (3j) and 4-fluoro (3o) phenyl boronic acids,12
provided the three-component coupling products in good
yields. The use of an arylboronic acid pinacol ester (Bpin) is
also effective (3c) in comparable yields (87% for Bpin and 95%
for B(OH)2).
Table 1. Reaction Optimization
a
entry
1
ligand
base
KF
yield of 3a (%)
ratio 3a:5a
−
−
30
25
57
0
3a only
3a only
60:40
b
2
KF
3
4
5
6
7
8
9
PPh3 (20 mol %)
P(tBu)3 (20 mol %)
P(Cy)3 (20 mol %)
dba (15 mol %)
K2CO3
K2CO3
K2CO3
K2CO3
NaHCO3
NaHCO3
−
c
5a only
19
70
82
50
40
90
30:70
3a only
3a only
3a only
3a only
3a only
dba (15 mol %)
dba (15 mol %)
dba (15 mol %)
d
10
NaHCO3
a
b
Determined by NMR using an internal standard. Reaction
c
performed at 30 psi. Heck product was observed in 21% yield.
d
The reaction was performed at 0.1 M in 1a.
To further explore the scope, vinyl boronic acid derivatives
were evaluated under the optimized conditions. In general, the
reaction performs similarly to aryl boronic acid derivatives to
yield skipped-diene products. For example, high yields using
(E)-β-styryl (3s) and simple (E)-alkenyl boronic acids (3t) are
observed but with significantly lower regioselectivity for
formation of the endo- versus exocyclic products (Figure 1).
The origin of this result is not currently understood. Cyclic
vinyl boronic esters (Bpin) having heteroatoms such as oxygen
and Boc protected nitrogen serve as effective coupling partners
(3u, 3v).
affect the electrophilic nature of the Pd(II) species presumably
required for efficient reaction due to the electron-poor nature
of this ligand.10 Indeed, addition of dba considerably enhanced
the reaction outcome (entry 6). Further improvements were
found by changing the base (entry 7) and increasing the
concentration of the vinyl triflate (entry 10). Removal of either
dba (entry 8) or the base (entry 9) resulted in significantly
lower yields.
Using the optimized conditions, the scope of the three-
component coupling was explored, where phenyl boronic acid
yielded the desired product in high yield and selectivity (Table
2, 3a). Excitingly, the more stable and cost-effective nonaflates
(ONf) are similarly effective electrophiles (3a).11 Both vinyl
To further examine and expand the scope of the reaction, the
use of heteroaromatic organometallic reagents was considered,
Table 2. Scope (Yields Average of at Least Two Experiments)
a
b
Represents the regioselectiviy of 3:4. Regioselectivity determined by 1H NMR of the crude reaction mixture. 4-Methoxy phenylboronic acid
c
pinacol ester yields the desired compound (3c) in 87% yield and similar regioselectivity. Boronic acid pinacol ester was used. Note: (1) For 3b−3e,
3g, 3i, 3m−3q, vinyl triflates were used; for 3f, 3h−3l, 3r, vinyl nonflates were used. (2) For products 3a−3i, yields are reported as a mixture of
regioisomers. For products 3j−3r, yields are reported as only the desired three-component coupling product. (3) The products were accompanied
by polyethylene as a contaminant (see Supporting Information for details).
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Table 3. Scope of Three-Component Coupling of Heteroaryl
Boronic Acid Pinacol Ester, Vinyl Nonaflates, and Ethylene
Figure 1. Scope of the three component coupling of ethylene, vinyl
nonaflates, and vinyl boronic acids/esters. The regioselectivity of 3:4 is
in parentheses. For 3s and 3t, boronic acid was used. For 3u and 3v,
boronic acid pinacol ester was used. Note: (1) In the case of 3u and 3v,
cyclohexenyl nonaflate was used as an electrophile. (2) Yields are
reported as a mixture of regioisomers. (3) The products were
accompanied by polyethylene as a contaminant.
a
b
Reaction performed at 55 °C for 16 h. Reaction performed at 55 °C
c
using CsF as base. The products were accompanied by polyethylene
as a contaminant.
as they pose a greater challenge and allow access to
considerably more structurally diverse products. Significant
issues have been encountered in Suzuki reactions employing
these reagents, as their Lewis basicity, slow rate of trans-
metalation, and ability to undergo protodeborylation all have
been proposed to limit their successful coupling. Ligand-
controlled solutions to some of these issues have been reported
recently by the groups of Buchwald,13 Fu,14 Plenio,15 and
others.16
the reaction is now effective (eq 2). The overall success of this
cross-coupling reaction in the absence of bulky, electron-rich
Indeed, in our previous efforts with terminal alkene three-
component couplings,6a reactions of heteroaromatic boronic
acids like 6a fail to yield the desired product with low
conversion of the vinyl triflate observed. Therefore, it was not
surprising that a low yield of the ethylene difunctionalization
reaction with 6a was found (eq 1). However, a modest change
phosphine ligands is in great contrast with that which has been
reported in the cross-coupling of heteroaromatic partners
suggesting some unique mechanistic features of this reaction.
In summary, we have developed a catalytic method that
utilizes ethylene as a substrate in a three-component cross-
coupling reaction to rapidly access structurally unique
compounds containing various pharmacophores under study
in our laboratory.6c In this vein, the scope of the reaction is
broad, allowing for the vinylarylation and vinylvinylation of
ethylene, as well as the extension to heteroaromatic coupling
partners by employing boronic ester derivatives. This advance
not only clearly impacts a major limitation of our previous
efforts in terms of scope but also opens up intriguing
mechanistic questions. Considering this, future work is focused
on expansion of the scope and understanding the underlying
means by which this cross-coupling operates to facilitate this
effort and the development of an enantioselective variant.
from the boronic acid to the pinacol ester (Bpin) led to the
successful three component coupling of these reagents (eq 1),
allowing for a significant expansion of the scope, as depicted in
Table 3. Surprisingly, under these reaction conditions, only a
single regioisomer is observed. Increasing the reaction time (36
h) and temperature (75 °C) allowed for enhanced yields.
Various heterocyclic boronic esters perform well under these
conditions as demonstrated by the use of five-membered
heterocycles (7b−7d). In addition, the more challenging
substrates 3-quinoline (7e) and a 2-substituted 4-pyridyl (7f)
boronic ester gave excellent yields of the desired product.
However, the reaction is sensitive to the nature of the
nucleophile as the reaction of 3-pyridineboronic ester and 3-
isoquinoline boronic ester produced low yields (<10%) of the
desired three-component coupling products. Of interest, 2-
pyridyl boronic acid derivatives have been found to be highly
prone to protodeborylation17 and in the current system are not
compatible with the reaction. However, replacement of the
Bpin derivative with the Stille reagent led to an excellent yield
of the three-component coupling of ethylene (7g). Finally, to
explore if the changes in the reaction conditions can be
extended to a simple terminal alkene, dodecene was evaluated
with 6a. Using only a single equivalent of the terminal alkene,
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for new
substances. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
sigman@chem.utah.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Institutes of Health
(NIGMS RO1 GM3540).
■
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Journal of the American Chemical Society
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