Palladium-Catalyzed One-Pot Carbonylative Sonogashira Reaction Employing Formic acid as the CO Source

Article abstract of DOI:10.1002/asia.201500518

A convenient palladium-catalyzed carbonylative coupling of aryl iodides and terminal alkynes with formic acid as the CO precursor has been developed. A variety of alkynones were obtained in good yields in a one-pot manner for the first time. CO Confidenti

Full text of DOI:10.1002/asia.201500518

DOI: 10.1002/asia.201500518
Communication
Carbonylation
Palladium-Catalyzed One-Pot Carbonylative Sonogashira Reaction
Employing Formic acid as the CO Source
Xinxin Qi,[a] Li-Bing Jiang,[a] Chong-Liang Li,[a] Rui Li,[a] and Xiao-Feng Wu*[a, b]
carbon monoxide through ex-situ generation.[10] Herein, we
Abstract: A convenient palladium-catalyzed carbonylative
coupling of aryl iodides and terminal alkynes with formic
wish to report our newly developed palladium-catalyzed car-
bonylative Sonogashira method with formic acid as the CO
acid as the CO precursor has been developed. A variety of
source.[11] Notably, this is the first example of one-pot alky-
alkynones were obtained in good yields in a one-pot
nones synthesis with formic acid as the CO source.
manner for the first time.
The first carbonylative Sonogashira reaction was carried out
with iodobenzene and phenyl acetylene as the model sub-
strates, 1,1’-bis-(diphenylphosphanyl)ferrocene (DPPF) as the
Palladium-catalyzed carbonylation reactions play a crucial role
in advanced chemical synthesis and have drawn much atten-
tion in recent years.[1] This strategy has emerged as a straight-
forward and powerful tool for preparing a variety of organic
compounds containing a carbonyl group such as aldehydes, al-
kynones, amides, carboxylic acids, ketones, and their deriva-
tives.[2] Among these carbonyl compounds, alkynones are of
great interest owing to their wide appearance in biologically
active molecules[3] and as versatile intermediates in the prepa-
ration of natural products.[4] They also have been utilized in
the synthesis of numerous heterocycles such as furans, pyr-
roles, pyrazoles, and quinoline derivatives.[5] Thus, various pro-
tocols for alkynones synthesis have been developed, the tradi-
tional approach to prepare alkynones relies on transition-
metal-catalyzed coupling reaction of acid chlorides with termi-
nal alkynes or alknyl organometallic reagents.[6,7] However, the
acid chlorides are not stable and the reactions require relative-
ly harsh conditions. An alternative approach is the transition-
metal-catalyzed carbonylative Sonogashira reaction of organic
halides with terminal alkynes,[8] which is a more straightfor-
ward method. However, the most restricting aspect of these
protocols is that gaseous CO is required, which is toxic and dif-
ficult to handle. Thus, procedures with alternative CO sources
have been developed. The research groups of Kondo and
Larhed succeeded in using Mo(CO)6 as the CO source for the
carbonylative Sonogashira reaction.[9] Recently, Skrydstrup and
co-workers developed a two-chamber system that can realize
alkynones synthesis with near stoichiometric amounts of
ligand, Et3N as the base in the presence of formic acid, and
acetic anhydride with Pd(OAc)2 as the catalyst in toluene at
308C. Fortunately, the desired product was obtained in 33%
yield (Table 1, entry 1). Encouraged by this result, we continued
our studies with various mono- and bidentate phosphine li-
gands. It was noteworthy that the 1,5-bis(diphenylphosphino)-
pentane (DPPPE) ligand gave a slightly higher yield (Table 1,
entry 2), but other screened bidentate phosphine ligands pro-
vided lower yields (Table 1, entries 3–6). Gratifyingly, PPh3 ap-
peared to be the best ligand for this reaction, and produced
Table 1. Screening of reaction conditions.[a]
Entry
Ligand
Base
Solvent
Yield [%][b]
1
2
3
4
5
6
7
DPPF
DPPE
DPPP
Xantphos
XPhos
BINAP
PPh3
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
33
37
4
19
1
0
82
61[c]
0[d]
3
0
0
0
0
16
7
39
31
8
9
PCy3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
Et3N
DBU
Pyridine
K2CO3
NaHCO3
Et3N
Et3N
Et3N
Et3N
Toluene
Toluene
Toluene
Toluene
Toluene
THF
DMF
CH3CN
1,4-dioxane
10
11
12
13
14
15
16
[a] Dr. X. Qi, L.-B. Jiang, C.-L. Li, R. Li, Prof. Dr. X.-F. Wu
Department of Chemistry
Zhejiang Sci-Tech University
Xiasha Campous, Hangzhou 310018 (People’s Republic of China)
E-mail: xiao-feng.wu@catalysis.de
[a] Reaction conditions: iodobenzene (1.0 mmol), phenyl acetylene
(2.0 mmol), Pd(OAc)2 (3 mol%), ligand (6 mol%), base (5 equiv), HCOOH
(2.0 mmol), acetic anhydride (2.0 mmol), solvent (2 mL), 308C, 24 h. [b] GC
yield, with dodecane as the internal standard. [c] PPh3 (4 mol%). [d] no
ligand, 15 h.
[b] Prof. Dr. X.-F. Wu
Leibniz-Institut für Katalyse e.V. an der Universität Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201500518.
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Communication
the corresponding product with 82% yield (Table 1,
entry 7); while only trace amounts of alkynone was
formed with PCy3 as the ligand (Table 1, entry 8). To our
surprise, no product was observed with 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU), pyridine, K2CO3, or NaHCO3
as the base; this can be explained by the high basicity
of DBU and low solubility of inorganic bases (Table 1,
entries 9–12). Furthermore, screening of different sol-
vents showed that toluene is the optimal solvent
(Table 1, entries 13–16). Additionally, acid anhydrides
such as trimethylacetic anhydride, isobutyric anhydride,
butyric anhydride, propionic anhydride, and trifluoro-
acetic anhydride were tested, but improved results
were not achieved.
Table 2. Carbonylative Sonogashira reaction of aryl iodides and terminal alkynes.[a]
Entry Aryl iodides
Alkynes
Products
Yield [%][b]
1
80
2
68
69
51
58
58
62
57
48
43
With the optimized reaction conditions in hand, we
next investigated a variety of aryl iodides and alkynes
(Table 2). Both electron-donating and electron-with-
drawing groups are tolerated well to give the desired
alkynone products in good yields (Table 2, entries 2–5).
Aryl iodides with fluoro and chloro groups can smooth-
ly provide the desired products in 58% and 62% yields
(Table 2, entries 6 and 7). The substrates bearing an
ortho-group resulted in lower yield compared to meta-
and para-substituted substrates; this can be explained
by the steric hindrance (Table 2, entries 7 and 8 vs 9).
The substrate with a difluoro group at the ortho- and
meta-position decreased the yield to 43% (Table 2,
entry 10). Remarkably, the substrates containing
a phenyl moiety also worked well to provide the corre-
sponding product in 60% yield (Table 2, entry 11). Fur-
thermore, various terminal alkynes were examined sub-
sequently (Table 2, entries 12–18). It was noteworthy
that those substrates bearing a meta-substituted aryl
group worked better than ortho- and para-substitution
(Table 2, entries 12 vs 13 and 14). We also tested other
electron-rich groups including methyl, tert-butyl, and
methoxy, the desired alkynones can be isolated in
good yields (Table 2, entries 14–16). Moreover, sub-
strates with fluoro and chloro moieties gave the de-
sired products in 53% and 58% yields, respectively
(Table 2, entries 17 and 18). Bromobenzene was tested
as well, but no product was detected. However, a trace
amount of the desired alkynone can be produced with
1-acetyl-4-bromobenzene as the coupling partner with
phenyl acetylene under the same reaction conditions.
Concerning the reaction pathway, a plausible mecha-
nism is proposed and shown in Scheme 1. The catalytic
cycle starts with the oxidative addition of aryl iodide to
Pd0Ln to give an arylpalladium complex and then forms
an acylpalladium intermediate after the coordination
and insertion of CO. The final alkynones will be elimi-
nated after reductive elimination and meanwhile give
Pd0 for the next catalyst cycle. Here the CO is in situ
produced from acetic formic anhydride, which was in
situ obtained by the reaction of formic acid and acetic
anhydride.
3
4
5
6
7[c]
8
9
10
11
60
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Communication
In conclusion, we have developed a convenient pal-
ladium-catalyzed Sonogashira carbonylative coupling
reaction for the synthesis of alkynones. Formic acid has
been used as the CO source; the desired alkynones can
be isolated in moderate-to-good yields under mild re-
action conditions. Notably, this is the first example of
a one-pot carbonylative Sonogashira reaction with
formic acid as the CO source.
Table 2. (Continued)
Entry Aryl iodides
Alkynes
Products
Yield [%][b]
12
82
Experimental Section
Typical reaction procedure for carbonylative Sonoga-
shira reaction: Pd(OAc)2 (3 mol%) and PPh3 (6 mol%) were
transferred into an oven-dried tube and then flashed with
nitrogen. Toluene (2.0 mL), iodobenzene (1.0 mmol), phe-
nylacetylene (2.0 mmol), and Et3N (5.0 mmol) were added
into the reaction tube via syringe. Then a mixture of formic
acid (2.0 mmol) and acetic anhydride (2.0 mmol) was
stirred at 308C for 1.5 h, and added drop wise to the reac-
tion tube. The final mixture was stirred at 308C for another
17–24 h. After the reaction was complete, the reaction mix-
ture was filtered, concentrated, and purified by column
chromatography on silica gel (petroleum ether/ethyl ace-
tate 50:1) to give the pure product.
13
14
57
54
15
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Acknowledgements
16
17
18
50
53
58
The authors thank the financial supports from NSFC
(21472174), education department of Zhejiang Province
(Y201432060) and Zhejiang Sci-Tech University
(1206838-Y; 14062015-Y). X.-F Wu appreciates the gen-
eral support from Professor Matthias Beller in LIKAT.
Keywords: alkynones · carbonylation · carbonylative
sonogashira reaction · CO · palladium
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Manuscript received: May 19, 2015
Accepted Article published: June 10, 2015
Final Article published: July 2, 2015
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