Pd-Catalyzed Synthesis of Vinyl Arenes from Aryl Halides and Acrylic Acid

Article abstract of DOI:10.1002/chem.201902022

Acrylic acid is presented as an inexpensive, non-volatile vinylating agent in a palladium-catalyzed decarboxylative vinylation of aryl halides. The reaction proceeds through a Heck reaction of acrylic acid, immediately followed by protodecarboxylation of the cinnamic acid intermediate. The use of the carboxylate group as a deciduous directing group ensures high selectivity for monoarylated products. The vinylation process is generally applicable to diversely substituted substrates. Its utility is shown by the synthesis of drug-like molecules and the gram-scale preparation of key intermediates in drug synthesis.

Full text of DOI:10.1002/chem.201902022

A Journal of
Accepted Article
Title: Pd-Catalyzed Synthesis of Vinyl Arenes from Aryl Halides and
Acrylic Acid
Authors: Yang Gao, Yang Ou, and Lukas J Goossen
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To be cited as: Chem. Eur. J. 10.1002/chem.201902022
Link to VoR: http://dx.doi.org/10.1002/chem.201902022
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10.1002/chem.201902022
Chemistry - A European Journal
COMMUNICATION
Pd-Catalyzed Synthesis of Vinyl Arenes from Aryl Halides and
Acrylic Acid
Yang Gao,a Yang Ou and Lukas J. Gooßen*
Abstract: Acrylic acid is presented as an inexpensive, non-volatile
vinylating agent in a palladium-catalyzed decarboxylative vinylation of
aryl halides. The reaction proceeds via a Heck reaction of acrylic acid,
immediately followed by protodecarboxylation of the cinnamic acid
intermediate. The use of the carboxylate group as a deciduous
directing group ensures high selectivity for monoarylated products.
The vinylation process is generally applicable to diversely substituted
substrates. Its preparative utility is shown by the synthesis of drug-like
molecules and the gram-scale preparation of key intermediates in
drug synthesis.
reasonable selectivities for monoarylated products have been
reported using excess ethylene (Scheme 1b).[17]
a) Vinylation of aryl halides or pseudohalides using vinylmetallic reagents
[Pd] or [Ni]/L
Y = MgX, BR2, SnR3, SiR3
X = I, Br, Cl, OTf
or
X = MgX, B(OH)2
Y = Cl, Br, OTf
b) Vinylation of aryl halides using ethylene
[Pd]/L
pressure
X = I, Br
flammable gas
Substituted styrenes are key building blocks in organic synthesis,
and are widely used in the manufacturing of fine chemicals[1] and
polymers.[2] Moreover, the vinyl group can be used as a hub for
further functionalization, e.g. by olefin metathesis,[3 ] carboxyl-
ation,[ 4 ] (asymmetric) hydrofunctionalization,[ 5 ] or heterocycle
synthesis.[ 6 ] However, whereas expedient methods exist to
introduce substituted alkenyl arenes, e.g. α,β-unsaturated
carbonyl compounds or stilbenes,[ 7 ] the introduction of vinyl
groups into functionalized molecules is not at all trivial.
c) This work: Development of decarboxylative vinylations using acrylic acid
[M]
path A
path B
-CO2
[Pd]/L
[M]= Cu or Ag
[M]
-CO2
[Pd]/L
Scheme 1. Strategies for the vinylation of aryl halides.
Established methods to access these products include the
dehydration or Hoffmann elimination of a saturated precursor,[8]
carbonyl olefination, [9] and partial reduction of terminal alkynes.[10]
However, these methods are limited by the availability of suitable
precursors. Arguably, the most versatile synthetic entry to vinyl
arenes is the reaction of aryl halides or pseudohalides with
organometallic magnesium-,[11] boron-,[12] tin-,[13] or silicon-based
[14] vinylating reagents (Scheme 1a). However, these reagents all
have their individual drawbacks, including their high price, and
limited stability or functional group compatibility. The coupling of
vinyl halides with preformed aryl–metal species suffers from the
limited structural availability of the latter.[15] Therefore, a new,
generally applicable vinylation agent with the potential to avoid
stoichiometric organometallic reagents is highly desirable.
We reasoned that acrylic acid, produced on an annual scale
of more than a million tons, would be an ideal vinylating agent,
since it is inexpensive, non-toxic, non-volatile and easy to
handle.[18] However, all attempts to apply the decarboxylative
cross-coupling pathway established for biaryl synthesis to acrylic
acid – i.e. decarboxylation of a copper acrylate and transfer of the
vinyl group to an arylpalladium complex – have been frustrated by
the low reactivity of acrylic acid towards decarboxylation (Scheme
1c, path A).[19] Still, we reasoned that the targeted decarboxylative
vinylation might be possible via an alternative pathway, in which
the carboxylate acts as a deciduous directing group (Scheme 1c,
path B).[20]
L2Pd0
HX
oxidative
addition
The Heck reaction of aryl halides with ethylene would
constitute a particularly straightforward and inexpensive route to
vinyl arenes despite the difficult handling of this gaseous
reagent.[16] However, the competing double arylation with form-
ation of stilbenes is hard to suppress due to the low solubility of
ethylene in organic solvents and the high reactivity of the styrene
intermediates towards coupling with aryl halides. Nevertheless
base
CO2
protodecarboxylation
hydride
elimination
[M]
Scheme 2. Mechanistic outline for the envisioned processes.
[*]
Dr. Y. Gao, Y. Ou, Prof. Dr. L. J. Gooßen
Fakultät Chemie und Biochemie
Ruhr-Universität Bochum
Universitätsstr. 150, 44801 Bochum (Germany)
E-mail: lukas.goossen@rub.de
Scheme 2 details the mechanistic blueprint for this approach.
The electron-withdrawing COOH group should facilitate a Heck-
type vinylation of aryl halides with acrylic acid leading to the
corresponding cinnamate. Cinnamic acid derivatives have a
strong tendency towards protodecarboxylation,[21] a reaction that
has been described as early as 1865[22] and has been led to
[a]
Dr. Y. Gao
School of Chemical Engineering and Light Industry
Guangdong University of Technology, 510006, Guangzhou (China)
Supporting information for this article is given via a link at the end of
the document
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10.1002/chem.201902022
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synthetic maturity by Abbott and Johnson.[23] The key require-
ments of an effective catalyst system for the desired
transformation were identified to be that it (1) is just active enough
to catalyze the vinylation with acrylic acid, (2) does not mediate
any further coupling of the aryl bromide with styrenes or cinnamic
acids, (3) effectively promotes the protodecarboxylation of
cinnamic acids but not that of acrylic acid, and (4) operates under
sufficiently mild conditions to avoid unwanted oxidation or
polymerization of substrates and products. In an ideal case, the
decarboxylation would be promoted by the same palladium
catalyst that mediates the cross-coupling step.[24]
yields along with 4-methylcinnamic acid (4a) as the main
byproduct (entry 3). The selectivity for the decarboxylated product
3a could be improved by the right choice of base. Whereas
inorganic bases such as NaHCO3 or K2CO3 gave unsatisfactory
results (see Table S2 in SI), amines and multidentate amines
such as TMEDA and PMDTA, in particular, shifted the selectivity
towards the desired product (entries 3-6). The ligand at the
palladium center is also decisive. The use of Buchwald-type
ligands sharply increased not only the conversion but also the
selectivity in favor of the desired product 3a versus the cinnamate
4a (entries 7-10). Best results were obtained with DavePhos (L1).
Increasing the temperature to 130 °C led to further improved
yields (entry 11).
In the search for a catalyst system that fulfills the above
requirements, 4-bromotoluene (1a) and acrylic acid (2) were
chosen as model substrates, and various bases, ligands, and
additives were systematically investigated (Table 1).
Table 2. Scope of the reaction with regard to the aryl halide substrate [a]
Pd(OAc)2/DavePhos
PMDTA,TBAB
Table 1. Optimization of the vinylation conditions.[a]
NMP, 130 ?C, -CO2
3a-z, 3aa-ai
1
2
Pd(OAc)2/[M]/L
p-
p-TolBr
p-
base, additive(s)
-CO2
1a
2
3a
4a
3b, R = H, 78%b
3c, R = OMe, 76%
3d, R = SMe, 57%
3e, R = Ph, 71%
3f, R = n-Pr, 82%
3g, R = CF3, 69%b,d
T
(°C)
3a
(%)
4a
(%)
3n, 77%
3a, X = Br, 86%b
X = Cl, 45%b
X = I, 80%b
Ligand
Base
Additive(s)
3m, X = Br, 45%
10 mmol scale, 65%
X = Cl, 50%
1[b]
2[c]
3
PPh3
"
Et3N
Cu(OH)2/1,10-Phen
120
6
5
3h, R = Ac, 66%d
3i, R = CO2Et, 72%
"
AgOAc/K2CO3
"
6
63
29
35
46
45
23
20
19
56
12
0
3q, 47%
3p, 74%
( )2
3j, R = CN, 51%
3k, R = F, 81%b
3l, R = CO2H, 41%
"
"
–
"
18
18
31
38
70
66
64
22
76
86
3o, 60%
4
"
NH(iPr)2
–
"
3r, 55%
3s, R = Et, 41%c
3t, R = OMe, 30%c
5
"
TMEDA
–
"
6
"
PMDTA
–
"
3x, R = H, 61%
3y, R = OMe, 82%
7
L1
L2
L3
L4
L1
L1
"
"
"
"
"
"
–
"
3u, 46%
3z, 64%
3v, 69%
3w, 60%
8
–
"
9
–
"
3aa, X = Br, 54%
3ac, 76%
X = Cl, 40%
3ab, 43%
3af, 70%
10
11
12
–
"
–
130
TBAB
"
3ag, 70%b
3ae, 72%
3ad, 54%b
L1
L2
L3
L4
3ai, 38%
from cholesterol
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), Pd(OAc)2 (10 mol%), ligand
3aj, 49%
from estrone
3ah, 72%
(20 mol%), base (3 equiv.), NMP (2 mL), 12 h, yields determined by 1H NMR
[b]
spectroscopy using dibromomethane as an internal standard.
Cu(OH)2 (10
[a]
mol%), 1,10-Phen (10 mol%). [c] AgOAc (10 mol%), K2CO3 (15 mol%). 1,10-Phen
1,10-phenanthroline, TBAB tetrabutylammonium bromide, NMP N-
Reaction conditions: 1a (0.5 mmol), 2 (0.75 mmol), Pd(OAc)2 (10 mol%),
=
=
=
DavePhos (20 mol%), PMDTA (3 equiv.), TBAB (1 equiv.), NMP (2 mL), 130 °C,
12 h, isolated yields. X = Br unless otherwise noted. [b] 1H NMR yield. [c] 140 °C.
[d] n-Bu4PBr (1.0 equiv.).
methylpyrrolidone, TMEDA = N,N,N′,N′-tetramethylethylenediamine, PMDTA =
N,N,N′,N”,N”-pentamethyldiethylenetriamine.
Since the formation of palladium black was observed during
the reaction, various additives known to stabilize Pd were tested.
In this context, tetra-n-butylammonium bromide (TBAB) was best
at suppressing the precipitation of Pd, which is in line with
Control experiments demonstrate that state-of-the-art Pd/Ag
or Pd/Cu decarboxylative cross-coupling catalysts are almost
ineffective (entries 1 and 2). Under classical Mizoroki-Heck
conditions, the desired styrene 3a was obtained in encouraging
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10.1002/chem.201902022
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COMMUNICATION
previous investigations on this reagent in Heck reactions by
Jeffery et al.[25] Thus, 3a was obtained in 86% yield (entry 12),
without even trace formation of 4a (see also Table S3 in SI).
Another control experiment confirmed that 4a is converted into 3a
under the decarboxylative vinylation conditions (Scheme 5a).
Further experiments revealed that both Pd and the P-ligand are
essential
for
both
the
cross-coupling
and
the
We next investigated the scope of the decarboxylative
vinylation. As can be seen from Table 2, the reaction protocol is
widely applicable to electron-rich and electron-deficient aryl
bromides bearing a wide variety of functional groups, such as
ether, ester, carbonyl, thioether, sulfone, cyano, trifluoromethyl,
and acetamido groups. Substituents in ortho-, meta-, and para-
position are tolerated. However, the yields of ortho-substituted
vinyl arenes were somewhat lower, presumably due to steric
hindrance. Even sensitive functionalities such as acidic -COOH
and -OH groups did not interfere with the reaction. The
decarboxylation process is highly chemoselective, affecting
neither benzoic nor aliphatic carboxylate groups in the substrates
(3l, 3ab, 3r).[26] 1,4-Divinylbenzene was obtained when using the
corresponding dihaloarene as substrate (3ad). Heteroaryl
bromides were also smoothly converted, as demonstrated by the
synthesis of vinyl furan, quinolone, thiophene and carbazole
derivatives (3ae-3ah).
protodecarboxylation. This is in line with Croatt’s mechanistic
proposal for the Pd/phosphine-catalyzed protodecarboxylation of
polyenoic acids,[24] which involves a reversible Michael addition of
the phosphine to the unsaturated carboxylates. Interestingly,
decarboxylation of 4a gave higher yields when it was added to a
decarboxylative cross-coupling of an aryl bromide and acrylic acid
(Scheme 5b). This suggests that the aryl bromide keeps the Pd
catalyst in oxidation state +2, which is likely to be the one required
for the protodecarboxylation step. All findings are consistent with
the proposed catalytic cycle (Scheme 2).
a)
Conditions
yield of 3a
standard conditions
without Pd(OAc)2
52%
0%
0%
protodecarboxylation
12 h, NMP, -CO2
p-
p-
b)
without DavePhos
without PMDTA base
3a
4a
23%
1b
2
standard conditions
p-
p-
4a
3a, 98%
3b, 81%
The reaction can also be used for the vinylation of alkenyl
bromides, providing convenient access to valuable dienyl arenes
(Scheme 3).[27]
Scheme 5. Mechanistic studies.
Pd(OAc)2/DavePhos
PMDTA,TBAB
In conclusion, utilizing carboxylates as deciduous directing
group opens up a convenient synthetic access to substituted
styrenes from widely available aryl halides and inexpensive and
easy-to-handle acrylic acids. Key features of the Pd-catalyst
system are that it favors the arylation of acrylic acid over that of
the styrene product and that it facilitates decarboxylation of the
cinnamic acids before an unwanted second arylation can occur.
NMP, -CO2
5
6a, R = H, 48%
6b, R = F, 50%
2
Scheme 3. Vinylation of alkenyl bromides.
The synthetic value of vinyl arenes is illustrated by the follow-
up reactions summarized in Scheme 4. Vinyl arene 3y was
synthesized from the corresponding aryl bromide in 70% yield on
gram scale, and was then further derivatized via
Experimental Section
28
]
hydrodroxythiolation, hydroxyacyloxylation, and nitration.[
An oven-dried 20 mL vial was charged with Pd(OAc)2 (11.2 mg, 0.05 mmol),
DavePhos (40.2 mg, 0.10 mmol) and TBAB (163 mg, 0.5 mmol) and closed with
a septum cap. Under argon, NMP (2.0 mL), aryl bromide (0.5 mmol, 1 equiv.),
PMDTA (0.32 mL, 1.5 mmol), and acrylic acid (52 µL, 0.75 mmol) were added,
and the mixture was stirred at 130 °C for 12 h. The resulting mixture was washed
with 1 M LiCl (15 mL) and 1 M HCl and the aqueous layer was extracted 3 times
with diethyl ether (10 mL). The combined organic phases were dried over
MgSO4, filtered, and the volatiles removed in vacuo. The residue was purified
by column chromatography (SiO2, pentane/ethyl acetate gradient).
Hydrocarboxylation of 3y furnished naproxen, a nonsteroidal anti-
inflammatory drug.[29]
ref. 23a
(a)
7, 87%
naproxen
(c)
(b)
10 mmol scale
3y, 1.29 g, 70%
Ar = 3-Cl-C6H4
Acknowledgements
8, 52%
9, 85%
t
Scheme 4. Synthetic applications. (a) PhSH, BuOLi, in EtOH, air, r.t.; (b) m-
Funded by the Deutsche Forschungsgemeinschaft (DFG,
German Research Foundation) under Germany‘s Excellence
Strategy – EXC-2033 – Projektnummer 390677874 and SFB‐
TRR 88 “3MET”. We thank UMICORE for donating chemicals,
BMBF and the state of NRW (Center of Solvation Science
“ZEMOS”), the CSC-DAAD (fellowship to Y.G.) and the CSC
(fellowship to Y.O.) for financial support, and Dr. A. Del Grosso
and M. Wüstefeld for spectroscopic measurements.
CPBA in DCM, r.t.; (c) AgNO2, TEMPO in DCE, 70 °C.
A series of experiments were conducted to elucidate the
reaction mechanism. A kinetic profile of the vinylation of 1a
showed that the substrates are rapidly consumed and that the
postulated cinnamic acid intermediate 4a indeed builds up in
solution (Figure S1 in SI). In the course of the reaction, 4a is
gradually consumed and the styrene product 3a is formed.
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Keywords: palladium • acrylic acid • aryl halides • vinylation •
decarboxylative coupling
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10.1002/chem.201902022
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Y. Gao, Y. Ou, L. J. Gooßen*
Pd(OAc)2/DavePhos
PMDTA,TBAB
NMP, -CO2
or
Page No. – Page No.
37 examples
up to 86%
Pd-Catalyzed Synthesis of Vinyl
Arenes from Aryl Halides and Acrylic
Acid
X = Br, Cl, I
Acrylic acid has been utilized as an inexpensive, non-volatile vinylating agent in a
palladium-catalyzed decarboxylative coupling with aryl halides. The reaction
proceeds via
a
Heck reaction of the acrylic acids and consecutive
protodecarboxylation of the resulting cinnamic acids. It is widely applicable to a wide
range of functionalized molecules leading exclusively to monoarylated compounds.
This article is protected by copyright. All rights reserved.