Palladium-catalyzed oxidative carbonylative coupling of arylboronic acids with terminal alkynes to alkynones

Article abstract of DOI:10.1039/c4ob01128g

We describe here an interesting palladium-catalyzed oxidative carbonylation of arylboronic acids with terminal alkynes. By the appropriate combination of a palladium salt, a ligand, and an oxidant, the desired alkynones were isolated in moderate to good yields. Notably, all the reactions were performed at room temperature, and moisture and air can be tolerated by this procedure. More importantly, this is the first example of oxidative carbonylative coupling of arylboronic acids with alkynes which filled the missing link in carbonylative coupling reactions. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob01128g

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Palladium-catalyzed oxidative carbonylative
coupling of arylboronic acids with terminal
alkynes to alkynones†
Cite this: Org. Biomol. Chem., 2014,
12, 5590
Received 2nd June 2014,
Accepted 17th June 2014
Kishore Natte, Jianbin Chen, Helfried Neumann, Matthias Beller and Xiao-Feng Wu*
DOI: 10.1039/c4ob01128g
www.rsc.org/obc
We describe here an interesting palladium-catalyzed oxidative with benzophenone and biphenyl.5c,d Recently, Yamamoto
carbonylation of arylboronic acids with terminal alkynes. By the reported the oxidative alkoxycarbonylation of arylboronates
appropriate combination of a palladium salt, a ligand, and an using a Pd(OAc)2/PPh3 catalyst and a stoichiometric amount of
oxidant, the desired alkynones were isolated in moderate to good benzoquinone as an oxidant.5f The desired products were
yields. Notably, all the reactions were performed at room tempera- obtained in good yields, and DFT as well as MP2 calculations
ture, and moisture and air can be tolerated by this procedure. More were carried out to understand the reaction mechanism. Later,
importantly, this is the first example of oxidative carbonylative Lei and co-workers developed an elegant methodology using
coupling of arylboronic acids with alkynes which filled the missing air as a benign oxidant in the presence of NEt3 as a base.5g
link in carbonylative coupling reactions.
More recently, our group reported the oxidative carbonylation
of arylboronic acids with styrenes.5h Chalcones were produced
in good to excellent yields using air as the oxidant. As our con-
tinuing interest in this area, here, we wish to report our recent
achievements on the oxidative carbonylation of arylboronic
acids with alkynes. By an appropriate combination of the cata-
lyst system and the oxidant, the desired alkynones were iso-
lated in moderate to good yields. Notably, this is the first
example of the oxidative carbonylative Sonogashira reaction.
Based on our experience on the oxidative carbonylation of
arylboronic acids with styrenes, we started our investigation
with ligand testing (Table 1, entries 1–6). Using Pd(OAc)2 as
the catalyst, Ag2O as the oxidant and NaOAc as the base, 42%
of the desired alkynone was formed with DPPP as the ligand
(Table 1, entry 2). And NaOAc was found to be the best base
for this transformation after testing several other typical bases
(Table 1, entries 7–11). Hex-1-yn-1-ylbenzene was detected as
the main by-product in all the cases.
Then different solvents were checked subsequently
(Table 2, entries 1–6), but no improved yield could be
observed. The commonly applied palladium salts were tested
as well (Table 2, entries 7–11), to our delight, 63% of 1-phenyl-
hept-2-yn-1-one was formed using Pd(TFA)2 as the catalyst
(Table 2, entry 11). Notably, the reaction was tested at 0 °C or
60 °C as well, but no better yield was detected. It is important
to mention that, in addition to the testing listed in Tables 1
and 2, DPPM, DPPPe, Xantphos, DPEPhos, PPh3, PCy3, bipyri-
dine, and 1,10-phen as ligands; CuO, Cu2O, Fe2O3, Cu(OAc)2,
BQ, TBHP (in decane), TBP, UHP (urea hydrogen peroxide),
Ag2CO3, AgOAc, AgNO3, Ag3PO4, and AgTFA as oxidants;
Cs2CO3, tBuOK, NEt3, NaHCO3, and KOAc as bases, and CO
Palladium-catalyzed carbonylation reactions have already
become a true toolbox in modern organic synthesis. These
transformations allow for the straightforward preparation of
aromatic carboxylic acid derivatives both on laboratory and
industrial scales.1 Among the developed palladium-catalyzed
carbonylative transformations of aryl halides, the carbonylative
Sonogashira reaction can give alkynones as their products
which are important compounds for heterocycle synthesis.2 In
all the known carbonylative Sonogashira reactions, ArX (X = I,
Br, OTf, N2OAc) are the commonly applied substrates.3 With
the concept of oxidative coupling, two nucleophiles are
coupled together in the presence of a suitable oxidant, the
carbonylative coupling of arylboronic acids with alkynes offers
another possibility.4 Notably, the formation of the respective
arylpalladium(II) complex as a crucial intermediate can be
achieved under milder conditions, because the related oxi-
dative addition to aryl halides is somehow a challenge in the
presence of CO.
As early as in 1981, Suzuki and co-workers reported the first
oxidative methoxycarbonylation of alkenylboron com-
pounds.5a,b Later on, Uemura and co-workers showed the
methoxycarbonylation of phenylboronic acid in methanol in
the presence of Pd(PPh3)4 and NaOAc as the catalytic system.
Here, methyl benzoate was obtained in 58% yield together
Leibniz-Institut für Katalyse an der Universität Rostock, Albert-Einstein-Straße 29a,
18059 Rostock, Germany. E-mail: xiao-feng.wu@catalysis.de
†Electronic supplementary information (ESI) available: Analytical data and NMR
spectrum. See DOI: 10.1039/c4ob01128g
5590 | Org. Biomol. Chem., 2014, 12, 5590–5593
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Table 1 Pd-catalyzed oxidative carbonylation of phenylboronic acid
with 1-hexyne: ligand and base testinga
Table 3 Pd-catalyzed oxidative carbonylation of arylboronic acid with
alkynes: substrate scopea
Entry
1
Products
Yieldb
54%
Entry
Ligand
Base
Yieldb
1
2
3
4
5
6
7
8
DPPE
DPPP
DPPB
DPPF
BINAP
BuPAd2
DPPP
DPPP
DPPP
DPPP
DPPP
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
tBuOK
Cs2CO3
Na2CO3
K2CO3
NEt3
5%
42%
8%
2%
0%
2
3
52%
58%
2%
14%
<1%
0%
4%
12%
9
10
11
a Pd(OAc)2 (2 mol%), ligand (4 mol%), base (2 equiv.), Ag2O
(1.5 equiv.), acetone (1 mL), CO (8 bar), phenylboronic acid
(0.5 mmol), 1-hexyne (1.2 equiv.), RT, 12 h. b Yields were determined
by GC using hexadecane as an internal standard, calculated based on
phenylboronic acid.
4
5
6
47%
61%
49%
Table 2 Pd-catalyzed oxidative carbonylation of phenylboronic acid
with 1-hexyne: solvent and palladium salt testinga
7
8
9
56%
62%
51%
Entry
[Pd]
Solvent
Yieldb
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd(MeCN)2Cl2
Pd(PPh3)2Cl2
PdCl2
MeCN
DMF
THF
EtOAc
Dioxane
DCM
Acetone
Acetone
Acetone
Acetone
Acetone
<1%
0%
23%
<1%
<1%
<1%
13%
5%
<1%
28%
63%c
10
11
12
73%
67%
78%
9
10
11
Pd(TFA)2
a [Pd] (2 mol%), DPPP (4 mol%), NaOAc (2 equiv.), Ag2O (1.5 equiv.),
solvent (1 mL), CO (8 bar), phenylboronic acid (0.5 mmol), 1-hexyne
(1.2 equiv.), RT, 12 h. b Yields were determined by GC using
hexadecane as an internal standard, calculated based on
phenylboronic acid. c Pd(TFA)2 (5 mol%), DPPP (10 mol%).
a Pd(TFA)2 (5 mol%), DPPP (10 mol%), NaOAc (2 equiv.), Ag2O
(1.5 equiv.), acetone (1 mL), CO (8 bar), arylboronic acid (0.5 mmol),
alkyne (1.2 equiv.), RT, 12 h. b Isolated yields.
pressure up to 40 bar were all tested with different combi-
nations, but no improved results were obtained.
With the best reaction conditions in hand, we carried out
the substrate testing (Table 3). The challenge of this transform-
ation was further proved by the difficulty in substrate testing. successful examples which showed excellent functional group
Among the examples of Ar(hetero)B(OH)2 tested (listed in tolerance and moderate yields of the alkynones were isolated.
ESI†), in most of the cases, the direct oxidative coupling of
Methylthio as a potentially oxidizable functional group can be
arylboronic acids with 1-hexyne are the main products tolerated under these oxidative coupling conditions (Table 3,
formed.6 Several selected examples are listed; however, the entry 3). Aryl halides, especially aryl iodides and aryl bromides,
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strates were purchased from Sigma-Aldrich and were used as
received. Solvents were dried using molecular sieves and kept
under argon. NMR spectra were recorded on Bruker AV 300
spectrometers. All chemical shifts (δ) are reported in parts per
million (ppm) and coupling constants (J) in Hz. All chemical
shifts are reported relative to tetramethylsilane (δ 0.0 for
1H NMR in DMSO-d6, CDCl3) and d-solvent peaks (δ 77.00 for
13C NMR, chloroform and δ 40.00 for DMSO-d6), respectively.
All measurements were carried out at room temperature unless
otherwise stated. Mass spectra were recorded on an AMD 402/3
or a HP 5989A mass selective detector. Gas chromatographic
analysis was performed on an Agilent HP-5890 instrument
with an FID detector and an HP-5 capillary column (poly-
(dimethylsiloxane) with 5% phenyl groups, 30 m, 0.32 mm
i.d., 0.25 mm film thickness) with argon as the carrier gas.
Scheme 1 Proposed reaction mechanism.
are typical substrates applied in palladium-catalyzed coupling
reactions.7 To our surprise, not only (4-chlorophenyl)boronic
acid but also (4-bromophenyl)boronic acid and (4-iodophenyl)-
boronic acid can be applied as substrates here; the corres-
ponding alkynones were isolated in 49–62% yields (Table 3,
entries 6–8). Instead of arylboronic acids, PhBF3K and phenyl-
boronic acid pinacol ester were tested with 1-hexyne under our
conditions as well. Unfortunately, only a trace of the desired
alkynone was formed and mainly resulted in a non-carbonyla-
tive coupling product. Additionally, several propargylic sub-
strates and phenylacetylenes were subsequently tested, but
only the direct oxidative coupling products were formed and
isolated in good yields (Table 3, entries 10–12).
Regarding the reaction mechanism, a possible reaction
pathway is proposed in Scheme 1. The reaction started with
Pd(II), and the acylpalladium was formed after transmetalation
with phenylboronic acid and insertion of CO. After an
exchange of the anion by phenyl acetylide, the desired product
was eliminated by reductive elimination. The Pd(0) was then
oxidized back to Pd(II) by Ag2O and was ready for the next
cycle. The cycle II gave the non-carbonylative coupling
product. Here, the transmetalation of the in situ generated
alkynylsilver with organopalladium species is too fast even at
room temperature, which may explain that the non-carbonyla-
tive products are the dominant products in most of the cases.
At the end of the reactions, a metallic silver ball and a silver
mirror can be observed.
Experimental section
The reaction was carried out in a Parr Instruments 4560 series
300 mL autoclave containing an alloy plate with wells for six
4 mL Wheaton vials. Pd(TFA)2 (5.0 mol%), DPPP (10.0 mol%),
Ag2O (2 equiv.), phenylboronic acid (0.5 mmol), NaOAc
(2 equiv.) and a magnetic stir bar were placed in each vial
under air, which were then capped with a septum equipped
with an inlet needle. Then 1-hexyne (1.2 equiv.) and acetone
(1 mL) were added to the vial via a syringe. The vials were
placed in an autoclave, filled with 8 bar of CO at room temp-
erature and the reaction was kept at room temperature for
12 h. After the reaction was complete, the autoclave was vented
to discharge N2. The product was extracted with ethyl acetate
(5 × 3 mL). The organic layers were washed with brine, dried
over Na2SO4, and evaporated to yield the crude reaction
mixture. The purification was done by flash chromatography
on silica gel (eluent: heptane–EtOAc 95 : 05).
Acknowledgements
We thank the state of Mecklenburg-Vorpommern and the Bun-
desministerium für Bildung und Forschung (BMBF) for finan-
cial support. We also thank Dr W. Baumann, Dr C. Fischer,
and S. Buchholz (LIKAT) for analytical support.
In conclusion, an interesting palladium-catalyzed oxidative
carbonylation of arylboronic acids with alkynes to give alky-
nones has been developed. By the appropriate combination of
a palladium catalyst, an oxidant and a base, the desired alky-
nones were isolated in moderate yields. Notably, this is the
first example of oxidative carbonylative coupling of arylboronic
acids with alkynes which filled the missed link in carbonyl-
ative coupling reactions.
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Reactions were performed under an air atmosphere with exclu-
sion of moisture from the reagents and the autoclaves. All sub-
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