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

Article abstract of DOI:10.1080/00397911.2012.745156

A mild and operationally simple procedure by Pd-catalyzed cross-coupling of acyl chlorides with in situ-generated alkynylzinc derivatives was developed, giving the corresponding ynones in good yields. Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications full experimental and spectral details.

Full text of DOI:10.1080/00397911.2012.745156

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Pd-Catalyzed Cross-Coupling of Acyl
Chlorides with In Situ–Generated
Alkynylzinc Derivatives for the Synthesis
of Ynones
Hu Yuan a b , Yunheng Shen b , Shichong Yu c , Lei Shan c , Qingyan
Sun c & Weidong Zhang a b
a School of Pharmacy , Shanghai Jiao Tong University , Shanghai ,
China
b Department of Phytochemistry , School of Pharmacy, Second
Military Medical University , Shanghai , China
c Department of Organic Chemistry , School of Pharmacy, Second
Military Medical University , Shanghai , China
Published online: 08 Jul 2013.
To cite this article: Hu Yuan , Yunheng Shen , Shichong Yu , Lei Shan , Qingyan Sun &
Weidong Zhang (2013) Pd-Catalyzed Cross-Coupling of Acyl Chlorides with In Situ–Generated
Alkynylzinc Derivatives for the Synthesis of Ynones, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 43:20, 2817-2823, DOI:
10.1080/00397911.2012.745156
To link to this article: http://dx.doi.org/10.1080/00397911.2012.745156
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Synthetic Communications1, 43: 2817–2823, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.745156
Pd-CATALYZED CROSS-COUPLING OF ACYL
CHLORIDES WITH IN SITU–GENERATED ALKYNYLZINC
DERIVATIVES FOR THE SYNTHESIS OF YNONES
Hu Yuan,1,2 Yunheng Shen,2 Shichong Yu,3 Lei Shan,3
Qingyan Sun,3 and Weidong Zhang1,2
1School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
2Department of Phytochemistry, School of Pharmacy, Second Military
Medical University, Shanghai, China
3Department of Organic Chemistry, School of Pharmacy, Second Military
Medical University, Shanghai, China
GRAPHICAL ABSTRACT
Abstract A mild and operationally simple procedure by Pd-catalyzed cross-coupling of
acyl chlorides with in situ–generated alkynylzinc derivatives was developed, giving the
corresponding ynones in good yields.
Supplementary materials are available for this article. Go to the publisher’s online edi-
tion of Synthetic Communications1 full experimental and spectral details.
Keywords Acyl chlorides; alkynylzinc; Pd-catalyzed; solvent-free; ynones
INTRODUCTION
Ynones are versatile building blocks for the synthesis of pharmaceutically
significant and biologically active compounds, such as pyrroles,[1] pyrazoles,[2]
isoxazoles,[3] pyrimidines,[4] quinolines,[5] and tetrahydro-b-carbolines.[6] Their prep-
aration typically involves the reaction of alkynyl organometallic reagents of silver,[7]
copper,[8] sodium,[9] lithium,[10] silicon,[11] tin,[12] cadmium,[13] or zinc[14] with acid
chlorides and transition-metal-catalyzed carbonylation of haloalkanes with terminal
alkynes in the presence of CO.[15] Most of the reported methods have poor yields, use
harsh conditions, or require long reaction times. Among many synthetic strategies,
Received August 22, 2012.
Address correspondence to Hu Yan or Weidong Zhang, School of Pharmacy, Shanghai Jiao Tong
University, Shanghai 200240, China, or to Qingyan Sun, Department of Organic Chemistry, School of
Pharmacy, Second Military Medical University, Shanghai 200433, China. E-mail: ahuoo86@163.com;
wdzhangy@hotmail.com; sqy_2000@163.com
2817

2818
H. YUAN ET AL.
the coupling reaction of acyl chlorides and terminal alkynes catalyzed by palladium
catalysts has received much attention of late. However, these methods require prep-
aration of some special heterogeneous catalysts[16] or conduct high temperatures.[17]
We hope to explore a mild and operationally simple procedure for the synthesis of
ynones using commercially available palladium catalysts.
The Pd-catalyzed cross-coupling of an organometal with an organic electrophile
has emerged over the past 30 years as one of the most general and selective methods
for carbon–carbon bond formation. Negishi et al.[18] reported a procedure for the syn-
thesis of ynones by Pd-catalyzed cross-coupling of organozincs with acyl chlorides,
but the procedure utilized organolithiums or Grignard reagents to form organozincs
compounds and needs harsh conditions. Herein, we report the Pd-catalyzed cross-
coupling of acyl chlorides with in situ–generated alkynylzinc derivatives for the
synthesis of ynones. The reactions are performed as a mild and operationally simple
procedure 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
To reduce the chance of reaction between the acyl chloride component and the
base,[19] we first tested the role of solvent for the coupling of benzoyl chloride (1b) with
phenyl acetylene (2a) (Table 1). It was noted that dichloromethane (DCM) and Et2O
were good solvents for this coupling reaction. However, dipolar aprotic solvents, such
as acetonitrile, dimethylformamide (DMF), and tetrahydrofuran (THF) gave inferior
results with the formation of the corresponding anhydride as a by-product. To our
surprise, when the reaction was performed under solvent-free conditions, the greatest
yield of product was obtained. Consequently, all further reactions were performed
neat under anhydrous conditions, and the results are recorded in Table 3.
A classical catalyst (Pd(PPh3)4) for Negishi reaction was employed in this work
and compound 3a was obtained in excellent yield without formation of benzoic
anhydride (Entry 1, Table 2). The reaction did not proceed without the Pd catalyst
and yielded only benzoic anhydride (Entry 2, Table 2). In 2006, S. S. Palimkar[20]
reported the palladium(II) acetate-catalysed acylation of terminal alkynes for the
synthesis of ynones using Et3N as base, but in our hand, only 60% yield of 3a and
Table 1. Coupling reaction of benzoyl chloride (1b) with phenyl
acetylene (2a) in the presence of different solventsa
Entry
Solvent
Yieldb (%)
1
2
3
4
5
6
Acetonitrile
DMF
THF
47
52
58
85
83
95
DCM
Et2O
Neat
aReaction conditions: acid chloride (1 mmol), 1-alkyne (1 mmol),
Pd(PPh3)4 (0.5 mol %), ZnCl2 (1.2 mmol), and Et3N (2 mmol), 30 min.
bIsolated yields.

SYNTHESIS OF YNONES
2819
Table 2. Synthesis of ynones by coupling of acid chlorides with terminal alkynesa
Entry
1
Acyl chloride
Alkyne
Product
Yieldb (%)
95
2
1a
89
3
4
1a
1a
88
94
5
6
7
1a
1a
1a
87
89
93
8
9
1a
1a
95
96
90
10
11
2a
2a
95
(Continued )

2820
H. YUAN ET AL.
Table 2. Continued
Entry
12
Acyl chloride
Alkyne
Product
Yieldb (%)
2a
89
13c
14
15
16
2a
2a
2a
2a
55
85
95
91
17
18
19
2a
2c
2d
92
93
98
1d
1d
20
21
22
1b
1c
1i
2 g
2f
93
92
88
2i
aReaction conditions: acid chloride (1 mmol), 1-alkyne (1 mmol), Pd(PPh3)4 (0.5 mol %), ZnCl2
(1.2 mmol), and Et3N (2 mmol), 30 min.
bIsolated yields.
cUse DIEA as base.

SYNTHESIS OF YNONES
2821
Table 3. Coupling reaction of benzoyl chloride (1b) with phenyl acetylene
(2a) in different conditionsa
Entry
Catalysts
Yieldb (%)
1
2
3
4
Pd(PPh3)4
c
—
95=0
0=37
d
Pd(OAc)2
Pd(PPh3)4
60=26
50=35
e
aReaction conditions: acid chloride (1 mmol), 1-alkyne (1 mmol), Pd
catalyst (0.5 mol %), ZnCl2 or ZnBr2 (1.2 mmol), and Et3N (2 mmol), 30 min.
bYnones yield=anhydride yield.
cNo catalyst was used.
dPalimkar’s method.
26% yield of benzoic anhydride were obtained (Entry 3, Table 2). Similarly, only 50%
yield of 3a and 35% yield of benzoic anhydride were obtained without ZnCl2
or ZnBr2 (Entry 4, Table 2) in this paper. So our method is highly effective for
the coupling reaction of acyl chlorides and terminal alkynes.
To examine the scope of this coupling reaction, various benzoyl chlorides 1
containing either electron-withdrawing or electron-donating groups were coupled
with different terminal alkynes 2 (Table 3). The results show that this reaction is
equally facile with both electron-donating and electron-withdrawing substituents
present on the acyl chloride and affords excellent yields of the corresponding ynones.
The reaction is tolerant of a wide range of functional groups on the acetylene
(Table 3), in particular aryl, alkyl, and heterocycle groups are compatible, all giving
isolated purified products in high yields. Hetero-aryl acid chloride (furoyl chloride
(Table 3, entry 12)) and a,b-unsaturated acyl chloride (p-methyl cinnamic chloride
(Table 3, entry 15)), reacted smoothly with phenyl acetylene to give the isolated
products in 89% and 95%, 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 chloride[19,21], whereupon a
satisfactory isolated yield of 3m was obtained (Table 3, entry 13).
In conclusion, we have developed a simple, efficient, and rapid solvent-free
synthesis of ynones at room temperature by the coupling of acyl chlorides with in
situ–generated alkynylzinc derivatives, catalyzed by Pd(PPh3)4 using Et3N as the
base. The simple procedure, short reaction times, good selectivity, and excellent
isolated yields make this method well suited for the generation of a combinatorial
library of ynones.
EXPERIMENTAL
A mixture of ZnCl2 or ZnBr2 (1.2 mmol) in Et3N (202 mg, 2 mmol) was stirred
for 10 min at room temperature. The reaction mixture was then successively treated
with alkyne (1 mmol), Pd(PPh3)4 (6 mg, 0.5 mol%) and acyl chloride (1 mmol), stirred
for 30 min at room temperature, diluted with Et2O, 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.

2822
H. YUAN ET AL.
Please see the Supporting Information, available online, for complete
experimental details.
ACKNOWLEDGMENTS
The work was supported by the NCET Foundation, NSFC (30725045), Global
Research Network for Medicinal Plants (GRNMP), King Saud University,
Shanghai Leading Academic Discipline Project (B906), FP7- PEOPLE-IRSES-
2008 (TCMCANCER Project 230232), Key Laboratory of Drug Research for Spe-
cial Environments, PLA, Shanghai Engineering Research Center for the Preparation
of Bioactive Natural Products (10DZ2251300), the Scientific Foundation of
Shanghai China (09DZ1975700, 09DZ1971500, 10DZ1971700), and the Twelfth
Five-Year National Science and Technology Support Program (2012BAI29B06).
REFERENCES
1. Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074–2075.
2. (a) Wang, X. J.; Tan, J.; Zhang, L. Org. Lett. 2000, 2, 3107–3109; (b) Grotjahn, D. B.;
Van, S.; Combs, D.; Lev, D. A.; Schneider, C.; Rideout, M.; Meyer, C.; Hernandez,
G.; Mejorado, L. J. Org. Chem. 2002, 67, 9200–9209.
3. Waldo, J. P.; Larock, R. C. Org. Lett. 2005, 7, 5203–5205.
4. (a) Bagley, M. C.; Hughes, D. D.; Taylor, P. H. Synlett 2003, 2, 259–261; (b) Karpov, A.
S.; Muller, T. J. J. Org. Lett. 2003, 5, 3451–3454; (c) D’Souza, D. M.; Muller, T. J. J.
¨
¨
Nat. Protocols 2008, 3, 1660–1665; (d) Karpov, A. S.; Muller, T. J. J. Synthesis 2003,
¨
2815–2826.
5. (a) Bagley, M. C.; Hughes, D. D.; Lloyd, R.; Powers, V. E. C. Tetrahedron Lett. 2001, 42,
6585–6588; (b) Arcadi, A.; Marinelli, F.; Rossi, E. Tetrahedron 1999, 55, 13233–13250.
6. (a) Karpov, A. S.; Oeser, T.; Muller, T. J. J. Chem. Commun. 2004, 1502–1503; (b)
Karpov, A. S.; Rominger, F.; Muller, T. J. J. Org. Biomol. Chem. 2005, 3, 4382–4391.
7. Davis, R. B.; Scheiber, D. H. J. Am. Chem. Soc. 1956, 78, 1675–1678.
8. (a) Normant, J. F. Synthesis 1972, 63–80; (b) Logue, M. W.; Moore, G. L. J. Org. Chem.
1975, 40, 131–132; (c) Bourgain, M.; Normant, J. F. Bull. Soc. Chim. Fr. 1973, 2137.
9. Fontaine, M.; Chauvelier, J.; Barchewitz, P. Bull. Soc. Chim. Fr. 1962, 2145.
10. Compagnon, P. L.; Grosjean, B.; Lacour, M. Bull. Soc. Chim. Fr. 1975, 779.
11. Walton, D. R. M.; Waugh, F. J. Organomet. Chem. 1972, 37, 45–56.
12. Logue, M. W.; Teng, K. J. Org. Chem. 1982, 47, 2549–2553.
13. Yashina, O. G.; Zarva, T. V.; Vereshchagin, L. I. Zh. Org. Khim. 1967, 3, 219; Chem.
Abstr. 1967, 66, 94664g.
14. Vereshchagin, L. I.; Yashina, O. G.; Zarva, T. V. Zh. Org. Khim. 1966, 2, 1895; Chem.
Abstr. 1967, 66, 46070p.
15. (a) Liang, B.; Huang, M. W.; You, Z. J.; Xiong Z. C.; Lu K.; Fathi R.; Chen, J. H.; Yang,
Z. J. Org. Chem. 2005, 70, 6097–6100; (b) Fusano, A.; Fukuyama, T.; Nishitani, S.;
Inouye, T.; Ryu, I. Org. Lett. 2010, 12, 2410–2411; (b) Wu, X. F.; Neumann, H.; Beller,
M. Chem. Eur. J. 2010, 16, 12104–12107.
16. (a) Santra, S.; Dhara, K.; Ranjan, P.; Bera, P.; Dash, J.; Mandal, S. K. Green Chem. 2011,
13, 3238–3247; (b) Bakherad, M.; Keivanloo, A.; Bahramian, B.; Rajaie, M. Tetrahedron
Lett. 2010, 51, 33–35; (c) Bakherad, M.; Keivanloo, A.; Bahramian, B.; Jajarmi S. Synlett
2011, 3, 311–314; (d) Keivanloo, A.; Bakherad, M.; Bahramian, B.; Rahmani, M.

SYNTHESIS OF YNONES
2823
Synthesis 2011, 2, 325–329; (e) Chen, J. Y.; Lin, T. C.; Chen, S. C.; Chen, A. J.; Mou,
C. Y.; Tsai, F. Y. Tetrahedron 2009, 65, 10134–10141.
17. Likhar, P. R.; Subhas, M. S.; Roy, M.; Roy, S.; Kantam, M. L. Helv. Chim. Acta 2008, 91,
259–264.
18. Negishi, E.; Bagheri, V.; Chatterjee, S.; Luo, F. T.; Miller, J. A.; Stoll, A. T. Tetrahedron
Lett. 1983, 24, 5181–5184.
19. Cox, R. J.; Ritson, D. J.; Dane, T. A.; Berge, J.; Charmant, J. P. H.; Kantacha, A. Chem.
Commun. 2005, 1037–1039.
20. Palimkar, S. S.; Kumar, P. H.; Jogdand, N. R.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V.
Tetrahedron Lett. 2006, 47, 5527–5530.
21. (a) Holder, R. W.; Freiman, H. S.; Stefanchik, M. F. J. Org. Chem. 1976, 41, 3303–3307;
(b) Suzuki, K.; Kitagawa, H.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1993, 66, 3729–3734.