A facile and efficient method for the synthesis of alkynone by carbonylative Sonogashira coupling using CHCl3 as the CO source

Article abstract of DOI:10.1039/c6ra02424f

A facile and efficient method for the synthesis of alkynones by a Pd-catalyzed carbonylative Sonogashira coupling reaction starting from aryl iodide, terminal alkyne and chloroform (CHCl₃) as the CO source is described. This procedure proves th

Full text of DOI:10.1039/c6ra02424f

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A facile and efficient method for the synthesis of
alkynone by carbonylative Sonogashira coupling
using CHCl3 as the CO source†
Cite this: RSC Adv., 2016, 6, 28442
Received 27th January 2016
Accepted 11th March 2016
*
*
Guanglong Sun, Min Lei and Lihong Hu
DOI: 10.1039/c6ra02424f
www.rsc.org/advances
A facile and efficient method for the synthesis of alkynones by a Pd- alkynones. High toxicity and pressure of CO severely limits the
catalyzed carbonylative Sonogashira coupling reaction starting from using of this method in organic synthesis. In recent years, to
aryl iodide, terminal alkyne and chloroform (CHCl3) as the CO source is avoid using CO directly, several precursors of CO have been re-
described. This procedure proves that CHCl3 is a cheap and efficient ported to replace the CO in organic synthesis.47–51 As shown in
CO source in the presence of CsOH$H2O as the base. Furthermore, it Scheme 1, methyldiphenylsilanecarboxylic acid,47,48 phenyl
is applied successfully for the modification of natural products, such as formate49 and 9-methyl-9H-uorene-9-carbonyl chloride50,51 are
vindoline and tabersonin, to obtain the corresponding products in applied successfully in organic synthesis as CO precursors.
good yields.
However, the use of these precursors has been limited due to
their high prices, especially on a large scale organic synthesis.
Therefore, there is a need to search a better precursor of CO for
the application in organic synthesis in terms of operational
simplicity and economic viability.
During the course of our studies, a Pd(II)-mediated carbon-
ylative Sonogashira coupling reaction for the synthesis of alky-
nones using CHCl3 as the CO precursor in the presence of
CsOH$H2O was also discovered.52–55 Herein, we describe a Pd(II)-
catalyzed carbonylative Sonogashira coupling reaction of aryl
iodide, terminal alkyne and CHCl3 to synthesis of alkynones.
Alkynones are important intermediates in various organic
syntheses of heterocyclic derivatives due to their multifunc-
tional nature, such as pyrimidines,1,2 quinolones,3 furans,4,5
pyrazoles,6–9 pyrroles,10,11 avones,12 and benzodiazepines.13
Furthermore, they are also used for the synthesis of many
natural products (e.g., azaspiracid,14 calystegine B2,15 anthra-
pyran metabolite16). In addition, alkynones have been reported
to possess diverse pharmacological properties such as antiin-
ammatory and analgesic activities,17 PKC inhibitors,18 CCR2
antagonists,19 and so on.20–23 Due to the unique structural
feature and also to the biological activities of alkynones,14–23 the
synthesis of alkynones has received a considerable attention.
Recently, many methods have been reported for the synthesis
of alkynones: (1) oxidation of propargylic alcohols;24–27 (2) reac-
tion of acyl chlorides with terminal alkynes;28–34 (3) reaction of
nitriles with terminal alkynes;35 (4) reaction of aldehydes with
terminal alkynes;36 (5) carbonylative Sonogashira coupling
reaction;37–41 (6) other methods.42–46 Among all of the methods
mentioned above, carbonylative Sonogashira coupling reaction
of aryl iodide, terminal alkyne and CO plays a key role due to its
good yields, mild reaction conditions, and excellent functional
group tolerance. However, a high CO pressure is always required
to achieve efficient carbonylative coupling for the preparation of
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, Shanghai, P. R. China. E-mail: mlei@simm.ac.cn; lhhu@simm.
ac.cn
† Electronic supplementary information (ESI) available: Experimental procedures,
copies of the 1H and 13C NMR spectra. See DOI: 10.1039/c6ra02424f
Scheme 1 Reported CO precursors.
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Initially, to exam whether the CHCl3 could be used as CO entries 5, 81 and 14), and toluene displayed the best solvent
precursor, we carried out the reaction of iodobenzene 1a, effect.
ethynylbenzene 2a, and CHCl3 using Pd(OAc)2 as catalyst,
In addition, the other factors, such as catalyst, base and
BINAP as ligand and CsOH$H2O as base in toluene. Aer stirred temperature, were also investigated and these contents were
ꢀ
for 8 h at 80 C, the desired product 3aa was obtained in 70% provided in ESI.† Having established the optimized reaction
yield. This result clearly indicated that CHCl3 could be as CO conditions, we then carried out the reaction under the similar
precursor to synthesis of alkynone. To further improve the conditions using aromatic compounds with different leaving
efficiency of this reaction, a series of optimization experiments groups, such as Br-, Cl-, TsO-, and TfO-, as substrates to replace
were performed, and the results are summarized in Table 1.
iodobenzene. In these cases, the results showed that only 1,4-
Preliminary experiments suggested that the ligands had diphenylbuta-1,3-diyne was obtained in 75% yield, and the
a signicant impact on the yields of 3aa. Hence, various ligands desired 3aa was not formed (see ESI†).
such as BINAP, dppf, dppp, PPh3, DPEphos, CEMTPP, (2-
To explore the generality and scope of the carbonylative
furyl)3P, and o-phenanthroline were applied to promote this Sonogashira coupling reaction, the reaction of various aryl
coupling reaction. As shown in Table 1, the reaction could not iodides and phenylacetylene was carried out under the optimized
proceed smoothly to obtain the corresponding product 3aa conditions (Table 2). As shown in Scheme 2, ortho, meta and para
under ligand-free conditions (Table 1, entry 1). All the ligands substituted substrates were chosen to exam the steric hindrance
studied on this reaction showed good ligand effect in terms of on this reaction. The desired products 3aa–na were obtained in
the yields of 3aa (50–96%) but o-phenanthroline (15%). By 78–91% yields. These results clearly indicated that the steric
screening of ligands, PPh3 was found to be the superior one
than others to obtained 3aa in 96% yield determined by LC-MS
and in 91% isolated yield, respectively. Therefore, PPh3 was
Table 2 Reaction of aryl iodides with ethynylbenzenea,b
chosen as the ligand for all further reactions.
Furthermore, to examine the solvent effect, various solvents
such as toluene, 1,4-dioxane, DMF, MeCN, EtOH, and THF were
applied to this coupling reaction. As shown in Table 1, the
reaction could not proceed smoothly in DMF and MeCN and
only 5% yield of 3aa was obtained in EtOH (Table 1, entries 11–
13). Moderate to excellent yields were obtained when using
toluene, 1,4-dioxane, and THF as the solvent (65–96%) (Table 1,
Table 1 Optimization of the reaction conditionsa
Entry
Ligand
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
—
BINAP
dppf
dppp
PPh3
DPEphos
CEMTPP
(2-Furyl)3P
o-Phenanthroline
PPh3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
1,4-Dioxane
DMF
0
70
80
76
96 (91)
85
91
50
15
81
0
9
10
11
12
13
14
PPh3
PPh3
PPh3
PPh3
MeCN
EtOH
THF
0
5
65
a
Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), CHCl3 (1.5 mmol),
a
Pd(OAc)2 (2.5 mol%), ligand (10 mol%), CsOH$H2O (5 mmol), solvent (3
Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), CHCl3 (1.5 mmol),
b
mL), 80 ꢀC, 8 h. Yields were determined by LC-MS; the number in Pd(OAc)2 (2.5 mol%), PPh3 (10 mol%), CsOH$H2O (5 mmol), toluene (3
b
parentheses refers to the yield of isolated 3aa.
mL), 80 ꢀC, 8 h. Isolated yields. c The reaction proceeded for 12 h.
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Scheme 3 Reaction of ethynylbenzene with natural products.
Scheme
2 Reaction of iodobenzene with substituted amino-
ethynylbenzene.
We further investigated the reactions of iodobenzene with
various terminal alkynes (Table 3). All of the aryl alkynes were
coupled with iodobenzene to afford the alkynones 3aa–ah in
good yields (86–92%). The reaction of 3-cyclohexyl-1-propyne
with iodobenzene proceeded to yield 72% of the desired
product 3ai.
hindrance of aryl iodides without signicant effect on this car-
bonylative Sonogashira coupling reaction. Moreover, both
electron-rich and electron-decient aryl iodides could afford the
corresponding alkynones 3aa–na in good yields (78–91%).
In addition, several substituted amino-ethynylbenzenes (2j,
2k and 2l) were selected for this reaction, and some interesting
results were obtained (Scheme 2). Normal product 3aj was
formed when using 3-(Boc-amino)-ethynylbenzene 2j as starting
material. However, only detriuoroacetyl product 3ak was ob-
tained under similar conditions when using 3-(triuoroacetyl-
amino)-ethynylbenzene 2j. If the amino without any protec-
tion group 2l, both 4aa and 3ak were formed in 80% and 10%
yields, respectively. These results provided an alternative
approach to synthesis corresponding products as needed.
Furthermore, this carbonylative Sonogashira coupling reac-
tion was also applied in natural products (Scheme 3). At rst,
vindoline and tabersonin were chosen as starting materials,
which were iodinated by NIS to form 15-iodo-vindoline 5 and 10-
iodo-tabersonin 6.56,57 Then, the reaction of 5 or 6 with phe-
nylacetylene was carried out under standard conditions for 12
h. The corresponding products 15-alkynone-vindoline 7 and 10-
alkynone-tabersonin 8 were obtained in 79% and 75% yields,
respectively.
Table 3 Reaction of iodobenzene with terminal alkynesa,b
Conclusions
In conclusion, we have developed a convenient and efficient
procedure for the carbonylative Sonogashira coupling of aryl
iodides with terminal alkynes using CHCl3 as the CO precursor.
It is noteworthy that this protocol is also suitable for the
modication of natural products. The mild reaction conditions,
short reaction time, high yields of the products, and compati-
bility with various functional groups, will make the present
a
Reaction conditions: 1a (0.5 mmol), 2 (0.6 mmol), CHCl3 (1.5 mmol),
Pd(OAc)2 (2.5 mol%), PPh3 (10 mol%), CsOH$H2O (5 mmol), toluene (3
mL), 80 ꢀC, 8 h. Isolated yields. c The reaction proceeded for 12 h.
b
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (grants 81273397 and 81561148011), the
Chinese National Science & Technology Major Project “Key New
Drug Creation and Manufacturing Program” (grant
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