Pd/BaSO4-catalyzed cross coupling of acyl chlorides with in situ generated alkynylzinc derivatives for the synthesis of ynones

Article abstract of DOI:10.1139/cjc-2012-0444

An efficient and operationally simple procedure using Pd/BaSO ₄-catalyzed cross coupling of acyl chlorides with in situ generated alkynylzinc derivatives was developed, giving the corresponding ynones at yields of 50%-96%.

Full text of DOI:10.1139/cjc-2012-0444

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Pd/BaSO4-Catalyzed Cross Coupling of
Acyl Chlorides with in Situ Generated
Alkynylzinc Derivatives For the Synthesis
of Ynones
Hu Yuan1,3, Huizi Jin1, Bo Li3, Yunheng Shen3, Rongcai Yue3, Lei Shan3, Qingyan
Sun2,*, Weidong Zhang1,3,
*
1School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China;
2Department of Organic Chemistry, School of Pharmacy, Second Military Medical
3
University, Shanghai 200433, China; Department of Phytochemistry, School of
Pharmacy, Second Military Medical University, Shanghai 200433, China.
Tel: +86ꢀ21ꢀ81871244; Fax: +86ꢀ21ꢀ81871244;
Email: wdzhangy@hotmail.com and sqy_2000@163.com
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Abstract: An efficient and operationally simple procedure by Pd/BaSO4ꢀcatalyzed
cross coupling of acyl chlorides with in situ generated alkynylzinc derivatives was
developed, giving the corresponding ynones in 50ꢀ96% yields.
Keywords: Pdꢀcatalyzed, heterogeneous catalyst, acyl chlorides, alkynylzinc, ynones
Introduction
Ynones
are
versatile
building
blocks
for
the
synthesis of
bioactive compounds with pharmaceutical applications, such as pyrroles1, pyrazoles2,
isoxazoles3, pyrimidines4, quinolines5, and tetrahydroꢀβꢀcarbolines6. Their preparation
typically involves the reaction of alkynyl organometallic reagents of silver7, copper8,
sodium9, lithium10, silicon11, tin12, cadmium13, or zinc14 with acid chlorides and
transitionꢀmetalꢀcatalyzed carbonylation of alkyl iodide with terminal alkynes in the
presence of poisonous carbon monoxide gas15. Among many synthetic strategies, the
coupling reaction of acyl chlorides and terminal alkynes catalyzed by palladium
catalysts has received much attention recently. In spite of the synthetic elegance of the
construction of synthetically useful ynones, these palladiumꢀcatalyzed reactions are
usually carried out in a homogeneous phase, which makes the catalysts difficult to
recover and reuse in more runs. Hence, facile separation of catalysts and products for
the recycling of the catalysts is rather important from the viewpoints of economical
and environmental concern. For these reasons, heterogenization of such homogeneous
catalysts used for ynone formation is very valuable. Recently, significant progress in
this area has been achieved with a variety of homogeneous palladium catalysts16.
However, the preparation and characterization of these homogeneous palladium
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catalysts were tedious.
In crossꢀcoupling reactions, particularly in the coupling of acyl chlorides with
terminal alkynes, commercially available catalysts Pd/C17, Pd on KF/Al2O3 have
18
been used as catalysts. While Pd/CaCO3 and Pd/BaSO4, known as catalysts in
hydrogenation19ꢀ21, are rarely or have not been utilized for the coupling reaction.
The Pdꢀcatalyzed crossꢀcoupling of an organometal with an organic electrophile
has emerged over the past thirty years as one of the most general and selective
methods for carbonꢀcarbonꢀbond formation. Negishi reported a method for the
synthesis of ynones by Pdꢀcatalyzed crossꢀcoupling of organozincs with acyl
chlorides22, but the method utilized harsh conditions to form organozinc compounds.
We recently reported the homogeneous Pd(PPh3)4ꢀcatalyzed cross coupling of acyl
chlorides with in situ generated alkynylzinc derivatives for the synthesis of ynones23.
In this paper, we describe the preparation of ynones via coupling of acyl chlorides
with in situ generated alkynylzinc derivatives, employing the heterogeneous
palladium complex as the catalyst. The reactions feature an operationally simple
procedure by using reaction of free alkynes with acyl chlorides in the presence of
premixed dry Et3N, ZnCl2 or ZnBr2, and a suitable Pd catalyst.
Results and discussion
In order to reduce the side reaction between the acyl chlorides and the base24, we
first screened solvents for the coupling of benzoyl chloride (1a) with phenyl acetylene
(2a) (Table 1). Triethylamine was found to be the best solvent for the reaction.
Unsatisfied yield of ynone and a considerable amount of benzoic anhydride were
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obtained if DCM, Et2O, toluene, CH3CN, THF or DMF was used as solvent.
Therefore, triethylamine could also be solvent in the reaction (Table 1).
Then different palladium catalysts were screened (Table 2). Among them,
Pd/BaSO4 afforded the best yield (entry 3). \ When the reaction was done without
ZnX2 or palladium catalyst, a low yield was obtained (Entry 4 and 5). Therefore,
ZnX2 and palladium catalyst are both necessary in the reaction.
To generalize the scope of our method, various benzoyl chlorides 1 containing
either electronꢀwithdrawing or electronꢀdonating groups were coupled with different
terminal alkynes 2 (Table 3). The results show that this reaction is equally facile with
both electronꢀdonating and electronꢀwithdrawing substituents present on the acyl
chloride and affords good to excellent yields of the corresponding ynones. The
reaction is tolerant to a wide range of functional groups on the acetylene (Table 3),
including aryl, alkyl, and heterocycle groups. Particularly heteroꢀaryl acid chloride
(furoyl chloride (Entry 11)) and α,βꢀunsaturated acyl chloride (pꢀmethyl cinnamic
chloride (Entry 13)), reacted smoothly with phenyl acetylene to give the isolated
products in 87 % and 90%, respectively. In the case of propionyl chloride, 1e, a bulky
diisopropylethylamine (DIEA) was employed instead of Et3N to avoid direct reaction
of the amine with the linear aliphatic acyl chloride24,25, whereupon a moderate
isolated yield of 3l was obtained (Entry 12, Table 3).
With the recycled catalyst, coupling of benzoyl chloride (1a) with phenyl acetylene
(2a), still gave the good yield in the fourth run without the significant loss of activity
(Table 4).
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Conclusion
In summary, we have developed a simple, efficient synthesis of ynones by the
coupling of acyl chlorides with in situ generated alkynylzinc derivatives, catalyzed by
Pd/BaSO4 using Et3N as the solvent and base. The catalytic system can be recycled up
to three times, showing a continuous slight decrease in activity The simple procedure
.
and excellent isolated yields make this method wellꢀsuited for the generation of a
combinatorial library of ynones.
Experimental section
General methods
All reactions were performed in dried small tube and monitored by TLC to ensure
the completion of the reaction. All solvents were dried and distilled according to the
standard methods before use. 5% Pd/BaSO4 and ZnX2 were obtained from Aldrich
Chemicals Co. Nuclear magnetic resonance (NMR) spectra were recorded using TMS
as the internal standard in CDCl3 with a Bruker BioSpin GmbH spectrometer at 300
or 500 MHz. When peak multiplicities are reported, the following abbreviations are
used: s = singlet, d = doublet, t = triplet, m = multiplet, dd = doublet of doublets;
ESIꢀMS was recorded on Agilent 1100 LC/MSD (70 ev) spectrometers. HRMS was
recorded on a Waters QꢀTof micro. Melting points (m.p.) were determined by
microscope melting point apparatus with aromatic temperature control system
(XT4A). Flash column chromatography was performed by using silica gel (200–300
mesh).
General procedure for the synthesis of ynones
A mixture of ZnCl2 or ZnBr2 (1.1 mmol) in Et3N (303 mg, 3 mmol) was stirred for
10 mins at room temperature. The reaction mixture was then successively treated with
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Alkyne (1 mmol), 5% Pd/BaSO4 (0.02 mmol; 42 mg) and Acyl chloride (1 mmol),
stirred for 60 mins at 80 °C, diluted with Et2O after cooling, washed with aqueous
NH4Cl and then with aqueous NaHCO3, dried over MgSO4, filtered, and concentrated
under vacuum to give the product which was further purified by column
chromatography using hexane/EtOAc (20:1) as eluent (spectra and characterization
data can be found in the Supplementary data).
Acknowledgements
The work was supported by program NCET Foundation, NSFC (81230090), partially
supported by Global Research Network for Medicinal Plants (GRNMP) and King
Saud University, Shanghai Leading Academic Discipline Project (B906), FP7ꢀ
PEOPLEꢀIRSESꢀ2008 (TCMCANCER Project 230232), Key laboratory of drug
research for special environments, PLA, Shanghai Engineering Research Center for
the Preparation of Bioactive Natural Products (10DZ2251300), the Scientific
Foundation of Shanghai China (09DZ1975700, 09DZ1971500, 10DZ1971700),
National Major Project of China (2011ZX09307ꢀ002ꢀ03) and National Key
Technology R&D Program of China (2012BAI29B06).
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Table 1. Coupling reaction of benzoyl chloride (1a) with phenyl acetylene (2a) in
different solventsa.
Entry
Solvent
DCM
Et2O
Yieldb (%)
1
2
3
4
5
6
7
57c
42c
58
38
43
34
92
Toluene
CH3CN
THF
DMF
Et3N
a Reaction conditions: acid chloride (1 mmol), 1ꢀalkyne (1 mmol), 5% Pd/BaSO4 (2
mol %), ZnCl2 (1.1 mmol) and Et3N (3 mmol), 80 °C, 60 min.
b Isolated yields.
c Refluxed at 40 °C for 180 mins.
Table 2. Coupling reaction of benzoyl chloride (1a) and phenyl acetylene (2a) with
different catalystsa.
Entry
Catalysts
Pd/C
Yieldb (%)
1
2
3
4
5
85
72
92
20
33
Pd/CaCO3
5% Pd/BaSO4
ꢀc
d
5% Pd/BaSO4
a Reaction conditions: acid chloride (1 mmol), 1ꢀalkyne (1 mmol), Pd catalyst (2
mol %), ZnCl2 and Et3N (3 mmol), 80 °C, 60 min.
b Isolated yields.
c Only ZnCl2 was used.
d No ZnCl2 was used.
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Table 3. Synthesis of ynones by coupling of acid chlorides with terminal alkynesa.
Entry
1
Acyl chloride
Alkyne
Product
Yieldb (%)
92
1a
1a
1a
1a
2a
3a
2
87
Br
2b
2c
3b
3c
3
4
89
91
2d
2e
2f
3d
O
5
6
7
1a
1a
88
85
90
S
3e
3f
1a
2g
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3g
3h
3i
8
9
1a
1a
91
92
91
87
50
90
93
2h
2i
10
11
12c
13
14
2a
1b
3j
2a
2a
2a
2a
1d
1e
3k
3l
1g
1h
3m
3n
12

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15
2a
91
1i
3o
3p
16
17
1d
2c
90
96
1d
1b
2d
3q
18
2g
87
90
3r
3s
19
1c
2f
a Reaction conditions: acid chloride (1 mmol), 1ꢀalkyne (1 mmol), 5% Pd/BaSO4 (2
mol %), ZnCl2 (1.1 mmol) and Et3N (3 mmol) , 80 °C, 60 min.
b Isolated yields.
c Use DIEA as base.
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Table 4. Coupling reaction of benzoyl chloride (1a) with phenyl acetylene (2a)
catalyzed by the recycled catalysta
Entry
Run
First
Yieldb/%
1
2
3
4
92
89
85
81
Second
Third
Fouth
a Reaction conditions: acid chloride (1 mmol), 1ꢀalkyne (1 mmol), 5% Pd/BaSO4 (2
mol %), ZnCl2 (1.1 mmol) and Et3N (3 mmol) , 80 °C, 60 min.
b Isolated yields.
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Table of Contents graphic
A simple, efficient synthesis of ynones was developed by the coupling of acyl
chlorides with in situ generated alkynylzinc derivatives, catalyzed by recyclable
Pd/BaSO4 using Et3N as the solvent and base.
15