Arylalkene synthesis via decarboxylative cross-coupling of alkenyl halides

Article abstract of DOI:10.1021/ol500876x

A bimetallic catalyst system generated from readily available palladium(II) and copper(I) salts, 1,10-phenanthroline and tri-1-naphthylphosphine was found to efficiently mediate the decarboxylative cross-coupling of alkenyl bromides and chlorides with aromatic carboxylates. It allows the regiospecific synthesis of a broad range of aryl- and heteroarylalkenes in high yields.

Full text of DOI:10.1021/ol500876x

Letter
pubs.acs.org/OrgLett
Arylalkene Synthesis via Decarboxylative Cross-Coupling of Alkenyl
Halides
Jie Tang and Lukas J. Gooßen*
Department of Organic Chemistry, TU Kaiserslautern, Erwin-Schrodinger-Str. Geb. 54, 67663 Kaiserslautern, Germany
̈
S
* Supporting Information
ABSTRACT: A bimetallic catalyst system generated from
readily available palladium(II) and copper(I) salts, 1,10-
phenanthroline and tri-1-naphthylphosphine was found to
efficiently mediate the decarboxylative cross-coupling of
alkenyl bromides and chlorides with aromatic carboxylates. It
allows the regiospecific synthesis of a broad range of aryl- and
heteroarylalkenes in high yields.
Scheme 2. Mechanistic Blueprint for a Decarboxylative
Alkenylation
ryl- and heteroarylalkenes are common structural subunits
1
2
Aof natural products, bioactive substances and functional
materials,3 and efficient synthetic entries to this important
moiety are constantly sought (Scheme 1).4 Industrially, aryl-
and heteroarylalkenes are prepared, for example, via dehydro-
genation reactions (a),5 condensations (b),6 or isomerizations
(c).7 Further established methods for the stereoselective
synthesis of arylalkenes include Wittig8 or Peterson olefinations
(d),9 carbometalations of alkynes (e),10 olefin metatheses (f),11
Heck reactions of aryl halides12 or carboxylates (g),13 and
transition metal-catalyzed cross-coupling reactions (h).14 Since
alkenyl halides are substrates easily accessible in defined
stereochemistries,15 their catalytic cross-coupling with organo-
metallic reagents has found widespread application, in particular
for the regiospecific arylation of alkenes.14 However, the
organometallic reagents, e.g., (hetero)arylzinc, -boron, or -tin
compounds, are often costly, hard to access, or sensitive to air
and moisture.
heteroatom bond formation.16 Their key advantage over
couplings of organometallic reagents is that the carbon
nucleophiles are generated in situ from widely available
carboxylate salts by extrusion of CO2. In the presence of a
suitable catalyst, usually a bimetallic copper/palladium or
silver/palladium system, various aromatic carboxylic acids have
successfully been coupled with a broad range of (hetero)aryl
halides17 and pseudohalides.18
Within recent years, decarboxylative coupling reactions have
emerged as a powerful new strategy for C−C and C−
Scheme 1. Synthetic Approaches to (Hetero)Arylalkenes
However, the substrate range of known catalyst systems does
not seem to extend to alkenyl halides. Cinnamyl bromides,
which must viewed as vinylogous aryl halides, are the sole
substrates for which successful decarboxylative cross-couplings
have been reported, namely, with cinnamic acids (Miura et
al.)19 and pentafluorobenzoic acid (Liu et al.).20 Myers’
decarboxylative Heck reaction was the first to give access to
vinylarene products from benzoic acids,13 but the regiochem-
istry of the arylation step depends on the steric and electronic
properties of the alkene, rather than being definable by a
leaving group.
Received: March 25, 2014
Published: May 6, 2014
© 2014 American Chemical Society
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Letter
a
a
Table 1. Optimization of the Reaction Conditions
Table 2. Scope with Regard to the Aromatic Carboxylates
entry
Cu-source
Pd-source
ligand
3aa (%)
b
1
CuBr
Pd(acac)2
−
−
dppm
19
48
71
44
63
46
73
69
63
67
68
71
75
83
87
79
81
92
97
99
74
83
2
“
“
3
“
“
4
Cu2O
“
“
5
CuOAc
“
“
6
CuI
“
“
“
7
“
“
8
“
Pd(dba)2
“
9
“
PdI2
“
10
11
12
13
14
15
16
17
18
19
“
PdBr2
“
“
PdCl2
“
“
Pd(OAc)2
“
“
Pd(F6-acac)2
“
“
“
“
“
“
“
“
“
“
“
PPh3
“
PCy3
“
P(t-Bu)3
“
P(p-Tol)3
“
P(o-Tol)3
“
P(1-naph)3
c
20
“
“
“
“
de
,
21
22
“
ef
,
“
a
Reaction conditions: 1a (0.6 mmol), 2a (0.5 mmol), Pd-source (1.0
mol %), phosphine ligand (2.0 mol %), Cu-source (10 mol %), 1,10-
phen (10 mol %), 4 mL of mesitylene/NMP 3:1, 120 °C, 16 h. Yields
determined by GC analysis using n-tetradecane as the internal
standard. phen =1,10-phenanthroline; dppm = bis(diphenylphos-
b
c
d
phino)methane. In NMP/quinoline 3:1. 130 °C. In situ generation
e
of 1a from the benzoic acid and K3PO4. With 200 mg of 4 Å
f
molecular sieves. Without drying and degassing.
An efficient and generally applicable protocol for the
decarboxylative cross-coupling of alkenyl halides would be
highly desirable, since it would allow the regiospecific synthesis
of arylalkenes starting from simple (hetero)aromatic carbox-
ylates. We believed that such a process should, in principle, be
possible if the decarboxylation step is mediated by copper and
the cross-coupling step by palladium (Scheme 2). The key to
success would be to synchronize the decarboxylation and cross-
coupling cycles.
a
Reaction conditions: 1 (0.6 mmol), 2 (0.5 mmol), Pd(F6-acac)2 (1.0
mol %), P(1-naph)3 (2.0 mol %), CuCl (10. mol %), 1,10-phen (10
b
c
mol %), 4 mL of solvent, 130 °C, 16 h. Isolated yields. 24 h. 150 °C.
d
e
CuI/PdBr2 as the catalyst. NMP/mesitylene 2:1.
In our search for a suitable catalyst system, we chose the
reaction of potassium 2-nitrobenzoate (1a) with 1-bromocy-
clohexene (2a) as a model and investigated various catalysts
that had proven to give excellent yields in analogous couplings
of 1a with aryl bromides.17a,21 However, as anticipated, they
displayed poor activity in the arylation of the cyclic alkenyl
bromide 2a. Using a combination of CuBr/1,10-phenanthroline
and Pd(acac)2 in a mixture of N-methylpyrrolidone (NMP)
and quinoline,21 only 19% yield were obtained at 120 °C
(Table 1, entry 1). A step-up in the yields was achieved by
reducing the solvent polarity and, thus, slowing down the
decarboxylation in relation to the cross-coupling step (Table 1,
entry 2). The addition of certain phosphine ligands such as the
bidentate bis(diphenylphosphino)methane (dppm) further
improved the yield to 71% (Table 1, entry 3). Copper sources
containing halide ions were found to be particularly effective,
and copper chloride provided the best yields (Table 1, entry 7).
Among the palladium precursors, Pd(F6-acac)2 proved to be
the optimal choice (Table 1, entries 8−13). An extensive ligand
screening revealed that the moderately electron-donating,
sterically demanding ligand tri-1-naphthylphosphine gave
higher yields than all phosphines previously employed in the
coupling of aryl halides (Table 1, entries 14−19). This suggests
that the oxidative addition, which is facilitated by particularly
electron-rich ligands, is not rate determining for alkenyl
bromides.
With the optimal catalyst system, 10 mol % copper chloride 1
mol % Pd(F6-acac)2 in NMP/mesitylene (1:3), full conversion
of 2a and near-quantitative yield of the desired 1-cyclohexenyl-
2-nitrobenzene (3aa) was reached within 16 h at 130 °C (Table
1, entry 20). Remarkably, considerable yields were obtained
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Letter
a
bromide salts has been reported to impede their decarbox-
ylation.17a,22
Table 3. Scope with Regard to the Alkenyl Bromides
The reaction is also widely applicable with regard to the
alkenyl bromides. As can be seen from the examples in Table 3,
mono-, di-, and even trisubstituted alkyl bromides gave similarly
high yields. Unwanted double bond isomerization, a common
side reaction in the alternative Heck reactions, did not take
place in significant amounts. The reaction proved to be high
yielding even for products that are inaccessible via decarbox-
ylative Heck reactions, e.g., cyclic arylalkenes or 2-arylalkenes,
thus demonstrating the complementarity of both approaches.
Only for highly volatile substrates, the isolated yields remained
unsatisfactory at 0.5 mmol scale, since the product partly
evaporated during work-up. The synthesis of 3ac in 80% yield
on a gram scale demonstrates that the reaction can easily be
scaled up.
Further studies revealed that only minor adjustments were
necessary to extend this reaction from alkenyl bromides to the
less costly, but also less reactive alkenyl chlorides. Thus,
representative alkenyl chlorides (4) were coupled with 2-
nitrobenzoic acid (1a) to give the products up to 92% yield in
the presence of 1 mol % Pd(TFA)2, 3 mol % tri-1-
naphthylphosphine, 3 mol % Cu2O and 5 mol % 1,10-
phenanthroline in NMP/mesitylene (2:1) at 150 °C (Scheme
3).
In conclusion, an efficient and broadly applicable protocol for
the decarboxylative cross-coupling of alkenyl bromides with
aromatic carboxylates has been developed. This reaction
provides an efficient, regiospecific entry to arylalkenes from
easily accessible aromatic carboxylates and alkenyl bromides or
chlorides.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data for the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
a
■
Reaction conditions: 1a (0.6 mmol), 2 (0.5 mmol), Pd(F6-acac)2 (1.0
S
mol %), P(1-naph)3 (2.0 mol %), CuCl (10 mol %), 1,10-phen (10
mol %), 4 mL of solvent, 130 °C, 16 h. Isolated yields. 10 mmol scale.
b
Scheme 3. Decarboxylative Couplings of Alkenyl Chlorides
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: goossen@chemie.uni-kl.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
already at 100 °C, which is an extremely low temperature for a
decarboxylative cross-coupling reaction (for more details, see
the Supporting Information). The reaction was also successfully
performed starting directly from the carboxylic acid and
without drying or degassing, which underlines its robustness
(Table 1, entries 21−22).
Having thus found an effective protocol for the decarbox-
ylative arylation of alkenyl bromides, we next investigated its
scope. As can be seen from the examples in Table 2, ortho-
substituted aromatic and heteroaromatic carboxylic acids
smoothly reacted with 1-bromocyclohex-1-ene (2a) or the
less volatile 3-bromo-1,2-dihydronaphthalene (2h) to give the
corresponding (hetero)arylalkenes. Ether, ketone, fluoro and
trifluoromethyl groups were tolerated, and the reaction
proceeds well even for sterically hindered o,o-disubstituted
benzoic acids. Non-ortho substituted benzoic acids could not
yet be converted, which was expected since the presence of
We thank the DFG (SFB TRR88 “3MET”) and the Chinese
Scholarship Council (fellowship to J.T.) for financial support.
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