A general and convenient palladium-catalyzed carbonylative sonogashira coupling of aryl bromides

Article abstract of DOI:10.1002/chem.201001864

Convenient carbonylations: An efficient methodology for the carbonylative Sonogashira reaction of aryl bromides has been developed (see scheme). Contrary to known procedures, inexpensive aryl bromides can be applied as substrates to give the desired compounds in moderate to good yields (47-88%).

Full text of DOI:10.1002/chem.201001864

DOI: 10.1002/chem.201001864
A General and Convenient Palladium-Catalyzed Carbonylative Sonogashira
Coupling of Aryl Bromides
Xiao-Feng Wu, Helfried Neumann, and Matthias Beller*[a]
Alkynones represent an interesting structural motif found
in numerous biologically active molecules.[1] Notably, this
class of compounds play a crucial role as key intermediates
in the synthesis of natural products[2] and in the efficient for-
mation of several heterocycles.[3] In the past alkynones have
been typically synthesised by transition-metal-catalyzed
cross-coupling reactions of acid chlorides and terminal al-
kynes (Scheme 1).[4] However, the stability of the respective
acid chlorides is limited and a lack of functional tolerance is
another problem of this methodology.
provements applying this methodology have been achieved.
For example, Ahmed and Mori described room temperature
reactions in the presence of 1 bar of CO.[6c] The groups of
Xia[6b] and Ryu[6j] developed a recyclable reaction system
with the assistance of Fe3O4 or in the presence of ionic liq-
uids. More recently, Ryu and co-workers also published the
synthesis of alkynones from iodoalkenes by applying a com-
bination of Pd/hv.[6m] In addition to palladium-based cata-
lysts copper was also described as an active metal for car-
bonylative Sonogashira reactions.[6n] Unfortunately, to date
most carbonylative Sonogashira reactions are strictly limited
to aryl iodides or iodoalkenes. So far, only a few exceptions
exist that require higher CO pressure (20–80 bar) and do
not proceed commonly in good yields.[6a] Clearly, aryl bro-
mides offer considerable advantages with regard to availa-
bility and costs compared with aryl iodides. Thus, a general
protocol for carbonylative Sonogashira couplings of aryl
bromides is of significant interest for both industrial and
academic communities.
Scheme 1. Selected synthesis and applications of alkynones.
Based on our recently developed palladium-catalyzed al-
koxycarbonylation with phenols,[7] we investigated the car-
bonylative Sonogashira reaction of bromobenzene and
phenyl acetylene with a catalyst system consisting of [(cinna-
myl)PdCl]2 (1 mol%) and BuPAd2 (di-1-adamantyl-n-butyl-
phosphine; cataCXium A; 6 mol%) in the presence of NEt3.
Unfortunately, only 13% of the desired carbonylative prod-
uct at 45% conversion was obtained (Table 1, entry 1). As a
major side-product the Hay/Glaser product (1,4-diphenylbu-
tadiyne) was observed. Notably, the product of the compet-
ing Sonogashira coupling (1,2-diphenylethyne) is not formed
under these conditions. Hence, we investigated the bench-
mark reaction further. To our delight simple variation of
base showed that inexpensive carbonates led to much im-
proved selectivity (Table 1, entries 2–4). For example, by
employing simple K2CO3 a 71% yield with 100% selectivity
is obtained (Table 1, entry 2). In the presence of this base,
we tested several mono- and bidentate ligands to improve
the yield further; however BuPAd2 appeared to be the best
ligand in this reaction (Table 1, entries 7–12). Remarkably,
the reaction temperature has a pronounced influence on this
Within the last two decades, palladium-catalyzed carbony-
lations of aryl halides have become a powerful toolbox for
the synthesis of all kinds of (hetero)aromatic carboxylic acid
derivatives.[5] In this respect, it has also been shown that pal-
ladium-catalyzed carbonylative Sonogashira reactions repre-
sent a viable alternative and efficient methodology for the
synthesis of alkynones. Advantageously, numerous such
starting materials are easily available and good functional
group compatibility has been demonstrated.[6] Since the first
report by Kobayashi and Tanaka in 1981,[6a] significant im-
[a] X.-F. Wu, Dr. H. Neumann, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Fax : (+49)381-1281-5000
E-mail: matthias.beller@catalysis.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001864.
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COMMUNICATION
Table 1. Variation of the reaction conditions.[a]
Table 2. Carbonylative Sonogashira reaction of various aryl bromides.[a]
Entry
Ligand [mol%]
Base
Conv. [%][b]
Yield [%][b]
En- Product
try
Yield En- Product
[%][b] try
Yield
[%][b]
1
2
3
4
5
6
7
8
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
PPh3
6
6
6
6
6
NEt3
45%
71%
30%
50%
20%
23%
69%
19%
26%
63%
30%
90%
82%
97%
87%
84%
13%
71%
23%
46%
7%
6%
14%
9%
12%
7%
0%
42%
52%
83%
71%
47%[d]
K2CO3
NaHCO3
Na2CO3
K3PO4
Cy2NEt
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
57%
1
2
81% 10
65% 11
88%[c]
6
6
PCy3
6
85%[c]
9
HPAd2
BzPAd2
DPPF
6
6
6
10
11
12
13[c]
14[c]
15[c]
16[c]
P
G
6
BuPAd2
BuPAd2
BuPAd2
BuPAd2
12
6
4
3
4
5
66% 12
75% 13
88% 14
80%[c]
6
[a] Bromobenzene (1 mmol), phenyl acetylene (1 mmol), [(cinna-
myl)PdCl]2 (1 mol%), ligand, base (2 equiv), DMF (2 mL), CO (10 bar),
1008C, 20 h. [b] Conversion and yield were determined by GC based on
bromobenzene with hexadecane as an internal standard. [c] [(Cinna-
myl)PdCl]2 (2 mol%). [d] CO (5 bar).
81%[c]
79%
model reaction: increasing the temperature to 1208C led to
the selective formation of (undesired) 1,2-diphenylethyne!
On the other hand, when we decreased the Pd/L ratio from
1:3 to 1:1.5 the yield of the carbonylative Sonogashira reac-
tion increased to 83% (Table 1, entry 14).
6
7
8
9
61% 15
76% 16
62% 17
68% 18
62%
With suitable conditions in hand (Table 1, entry 14), we
next employed different terminal alkynes and aryl bromides
in 18 carbonylative Sonogashira reactions. As shown in
Table 2 in general good to very good yields (47–88%) were
achieved. With respect to functional group tolerance, ether,
amino, alkyl and fluoride substituents were tolerated with-
out problems both in the alkyne and aryl part. ortho-Substi-
tuted aryl bromides also resulted in the corresponding alky-
nones with moderate to good yields (Table 2, entries 14–17;
47–79%). In addition, 3-bromothiophene (as an example of
a heterocyclic bromide) also worked in our system (Table 2,
entry 18). However, in this case a higher CO pressure
(30 bar CO) had to be applied. On the other hand p-CF3-,
p-CHO- and p-CN-substituted bromoarenes were not suc-
cessfully carbonylated under these conditions. Here, apart
from traces of the alkynones, a large amount of the respec-
tive Sonogashira coupling product was formed. 4-Chloroace-
tophone did not show any conversion.
55%[d]
47%[d]
53%[d]
[a] Aryl bromide (1 mmol), alkyne (1 mmol), [(cinnamyl)PdCl]2 (2 mol%),
BuPAd2 (6 mol%), K2CO3 (2 equiv), DMF (2 mL), CO (10 bar), 1008C, 20 h.
[b] Yield of the isolated product. [c] 1.5 equiv of alkyne. [d] 1158C, CO (30 bar).
Mꢀller and co-workers[8] as well as other groups[9] have el-
egantly demonstrated the potential of alkynones in hetero-
cycle syntheses. Hence, we performed exemplarily one-pot
syntheses of isoxazolines and pyrazoles starting from inex-
pensive aryl bromides (Scheme 2). Here, methylhydrazine,
phenylhydrazine, or hydroxylamine was added at the end of
the carbonylative Sonogashira reaction. After additional
stirring at room temperature for 1 hour, the corresponding
pyrazole and isoxazole products were successfully isolated
in high yield (75–81%).
With regard to the mechanism, we propose an initial oxi-
dative addition of the aryl bromide to the LPd0 species to
give the corresponding
arylpalladium(II) complex
(Scheme 3). Subsequent formation of the benzoylpalladium
complex takes place by CO insertion. Supported by K2CO3
an exchange of the bromide by phenyl acetylide occurs and
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M. Beller et al.
was adjusted and the reaction was per-
formed for 20 h at 1008C. After the re-
action, the autoclave was cooled down
to room temperature and the pressure
was released carefully. To the reaction
mixture 6 mL water was added and
the solution was extracted 3–5 times
with 2–3 mL of ethyl acetate. The ex-
tracts were evaporated with adsorption
on silica gel and the crude product
was purified by column chromatogra-
phy using n-heptane and n-heptane/
AcOEt (50:1) as eluent. The product
was obtained in 81% yield (167 mg) as
a yellow oil.
General procedure for the one-port
heterocyclic formation: After the car-
Scheme 2. One-pot synthesis of heterocycles.
bonylation reaction, the reaction mix-
ture was cooled to room temperature
and the pressure was released careful-
ly. Next, 1 mmol of methylhydrazine was added and stirring was contin-
ued at room temperature for 1 h. Water (2 mL) was added to the reaction
solution and the organic layer was extracted 3–5 times with of ethyl ace-
tate (2 mL). The extracts were evaporated with adsorption on silica gel
and the crude product was purified by column chromatography using n-
heptane and n-heptane/AcOEt (50:1) as eluent.
Acknowledgements
The authors thank the state of Mecklenburg-Vorpommern and the Bun-
desministerium fꢀr Bildung und Forschung (BMBF) for financial support.
We also thank S. Leiminger, K. Mevius, Dr. W. Baumann, Dr. C. Fischer
and S. Buchholz (LIKAT) for analytical support.
Scheme 3. Proposed reaction mechanism.
Keywords: alkynones · aryl bromides · carbonylation ·
palladium · Sonogashira reaction
the desired product is formed by reductive elimination. It is
worth mentioning that CO migration and insertion are con-
sidered to be reversible steps within this system. Since at
higher temperature (1208C) decarbonylation[10] is favoured
and only 1,2-diphenylethyne is formed, whereas at lower
temperature (808C) the carbonylation dominates and only
the alkynone is observed as product.
In conclusion, a novel chemoselective protocol for the car-
bonylative Sonogashira coupling of aryl bromides at low
pressure has been developed. The key to success is the ap-
plication of a palladium/BuPAd2 catalyst system[11] in the
presence of potassium carbonate as base.
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General procedure for carbonylative Sonogashira reactions: [(Cinna-
myl)PdCl]2 (10.3 mg, 2 mol%), BuPAd2 (22 mg, 6 mol%) and K2CO3
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Palladium-Catalyzed Carbonylative Sonogashira Coupling
COMMUNICATION
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Received: July 1, 2010
Published online: September 16, 2010
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