Palladium-catalyzed haloallylation of aromatic ynol ethers with allyl chlorides: A highly regio- and stereoselective approach to (1E)-α- chloroenol ethers

Article abstract of DOI:10.1039/c1cc13424h

Described herein is a Pd-catalyzed haloallylation of aromatic ynol ethers and allyl chlorides, allowing facile access to (1E)-α-chloroenol ethers in a highly regio- and stereoselective manner. The synthetic utility of this method is demonstrated well by t

Full text of DOI:10.1039/c1cc13424h

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Palladium-catalyzed haloallylation of aromatic ynol ethers with allyl chlorides:
a highly regio- and stereoselective approach to (1E)-a-chloroenol ethersw
Haiting Cai,a Zheliang Yuan,a Weidong Zhub and Gangguo Zhu*ab
Received 9th June 2011, Accepted 20th June 2011
DOI: 10.1039/c1cc13424h
Described herein is a Pd-catalyzed haloallylation of aromatic
ynol ethers and allyl chlorides, allowing facile access to (1E)-a-
chloroenol ethers in a highly regio- and stereoselective manner.
The synthetic utility of this method is demonstrated well by the
synthesis of the stereodefined multisubstituted enol ethers and
a-allylated carbonyl compounds.
The transition-metal-catalyzed reactions have become one of the
most powerful tools for the effective construction of carbon–
carbon or carbon–heteroatom bonds in organic chemistry.1 In
Scheme 1 Two pathways for halopalladation of acetylenes.
this respect, the halopalladation of acetylenes is receiving
considerable attention because of the highly efficient and atom-
of 5 mol% of PdCl2 in THF at 50 1C for 1 h gave (1E)-a-
chloroenol ether 3aa in 87% isolated yield (entry 1, Table 1).
economic formation of carbon–carbon and carbon–halide bonds
in a single step.2,3 Among these, particularly good selectivities
The regiochemistry of this reaction was determined by the
and high yields were obtained for terminal alkynes and alkynes
NOE experiments. Replacement of PdCl2 by other palladium
with electron-withdrawing groups. Less developed are the
catalysts, such as Pd(OAc)2, Pd(MeCN)2Cl2 and Pd(PhCN)2Cl2,
reactions with unsymmetrical internal alkynes, because the
led to lower yields (entries 2–4, Table 1). Further survey of the
control of regiochemistry is usually problematic.
solvents using PdCl2 as the catalyst concluded that THF was the
Fundamentally, the halopalladation of internal alkynes can
preferred medium for the reaction (entries 5–12, Table 1). As
proceed via two different types of pathways, i.e., a-addition
(palladium a to the Y group) and b-addition (Scheme 1). To
address this issue, quite recently, we successfully extended the
halopalladation reaction into unsymmetrical internal alkynes
by substituting the acetylenes with halogen atoms, where the
halopalladation of the CRC triple bond exclusively undergoes
the a-addition pathway.4 In contrast, the regioselective
halopalladation of acetylenes featuring the b-addition pathway
has not been achieved yet. Clearly, it would enhance the scope
and synthetic utility of halopalladation reaction if methods
permitting the b-addition products were developed. In this
communication, we report a highly regio- and stereoselective
palladium-catalyzed haloallylation5 of aromatic ynol ethers
with the formation of a b-addition adduct as the key intermediate.
We initially investigated the reaction parameters by
conducting the haloallylation reaction of 1-ethoxy-2-phenyl-
acetylene (1a) with allyl chloride (2a). To our delight, the use
such, the optimal reaction conditions consisted of 5 mol% of
PdCl2 as the catalyst, 50 1C as the reaction temperature, and
THF as the solvent.
Table 1 Optimization of the reaction conditionsa
Entry
PdX2
Solvent
Yieldb,c (%)
1
2
3
4
5
6
7
8
PdCl2
THF
THF
THF
THF
Dioxane
DCE
Toluene
CH3CN
EtOH
DMSO
EtOAc
DME
93 (87)c
80
85
83
62
30
81
84 (4/1)d
0
0
69
73
Pd(OAc)2
Pd(MeCN)2Cl2
Pd(PhCN)2Cl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
9
a Department of Chemistry, Zhejiang Normal University, 688 Yingbin
Avenue, Jinhua 321004, China. E-mail: gangguo@zjnu.cn;
Fax: +86-579-82282610; Tel: +86-579-82283702
10
11
12
b Key Laboratory of the Ministry of Education for Advanced Catalysis
Materials, Zhejiang Normal University, Jinhua 321004, China
w Electronic supplementary information (ESI) available: Experimental
details and characterization of new compounds. See DOI: 10.1039/
c1cc13424h
a
Reaction conditions: 1a (0.5 mmol), 2a (1.5 mmol), and Pd catalyst
b
(0.025 mmol) in 2 mL of solvent at 50 1C for 1À3 h. GC yield.
c
d
Isolated yield. Two stereoisomers (E/Z = 4/1) were obtained.
c
8682 Chem. Commun., 2011, 47, 8682–8684
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Table 2 Pd-catalyzed haloallylation of ynol ethers with 2aa
Table 3 Pd-catalyzed haloallylation of 1a with 2a
Entry
1
R
3
Yieldb (%)
Entry 2
3
Yieldb (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
Ph
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
3oa
87
78
85
81
76
68
83
79
82
74
76
72
77
75
0
4-Pr–C6H4
4-Me–C6H4
4-Br–C6H4
3-Br–C6H4
2-Br–C6H4
4-Cl–C6H4
2-Cl–C6H4
4-F–C6H4
3-OMe–C6H4
2,4-Cl2–C6H3
3,4-OMe2–C6H3
2-Thienyl
1
82c
2
73
71
0
9
10
11
12
13
14
15
3e
4e
5e
2-Naphthyl
n-C5H11
a
Reaction conditions: 1 (0.5 mmol), 2a (1.5 mmol), PdCl2 (0.025 mmol)
b
in 2 mL of THF at 50 1C for 1–3 h. Isolated yield.
With the optimized reaction conditions identified, the scope
and limitations of this approach were then investigated in detail
with other alkynyl ethers. As summarized in Table 2, the reaction
was suitable for a wide range of aromatic ynol ethers. Both
electron-rich and electron-deficient aromatic alkynyl ethers were
smoothly converted into the (1E)-a-chloroenol ether products
in good yields with excellent stereoselectivity (Table 2). For
example, ynol ethers 1b and 1c resulted in the desired (1E)-a-
chloroenol ethers 3ba and 3ca in 78% and 85% yields,
respectively (entries 2 and 3, Table 2). The reaction of sterically
hindered ynol ethers 1f and 1h occurred uneventfully as well,
producing (1E)-a-chloroenol ethers 3fa and 3ha in 68% and 79%
yields, respectively (entries 6 and 8, Table 2). Heteroaromatic
ynol ether, 1m, for example, led to the (1E)-a-chloroenol
ether 3ma in 77% yield (entry 13, Table 2). However, to our
disappointment, the reaction of aliphatic ynol ether 1o failed to
give the desired product, due to its oligomerization under the
standard reaction conditions (entry 15, Table 2).
0
6f
83g
a
Reaction conditions: 1a (0.5 mmol), 2 (1.0 mmol), PdCl2 (0.025 mmol)
b
c
in 2 mL of THF at 50 1C for 1À10 h. Isolated yield. 4E/4Z = 1.8/1.
d
f
e
2E/2Z = 2/1. The reaction was carried out at 70 1C for 10 h.
5 mol% of PdBr2 was used. 1E/1Z = 4/1.
g
be attributed to the increased polarity of the Pd–Br bond,3f that
is, the more polar Pd–Br bond may generate the free bromide ion
and lead to the formation of a (1Z)-isomer through the trans-
halopalladation process.6
The versatility of this method was further examined by the
reactions of 1a with various allylic halides (Table 3). As shown in
Table 3, 3-chloro-1-heptene (2b) produced the a-chloroenol ether
3ab in 82% yield with a 1.8/1 mixture of two stereoisomers (entry 1,
Table 3). Furthermore, the reaction is sensitive to the steric
and electronic effects of allyl halides. For example, 2-methyl-
substituted allyl chloride (2c) smoothly reacted with 1a at 50 1C
for 2 h to give the desired product 3ac in good yield, while the
reaction of crotyl chloride (2d) had to be performed at 70 1C
for 10 h to complete the conversion (entries 2 and 3, Table 3).
Additionally, both cinnamyl chloride (2e) and its isomer 2f were
intact under the reaction conditions even at a higher temperature
of 70 1C (entries 4 and 5, Table 3).
To demonstrate the synthetic utility of this method,
the resulting products were examined in the Pd-catalyzed
cross-coupling reactions. For example, the Suzuki–Miyaura
coupling7 of 3aa with 4-Me-C6H4B(OH)2 employing Xphos8
as the ligand gave the trisubstituted enol ether 4a in 77% yield,
while the Sonogashira coupling9 of 3aa with 1-hexyne afforded
the enol ether 4b in 82% yield (Scheme 2). Although there
are a few methods that exist for the synthesis of the highly
On the other hand, a-bromoenol ether 3ag could be generated
in 83% yield using allyl bromide (2g); however, a mixture of two
stereoisomers (1E/1Z = 4/1) was isolated (entry 6, Table 3).
In comparison to the (1E)-a-chloroenol ether products, the
inconsistency of this reaction in terms of stereoselectivity could
Scheme 2 Synthesis of stereodefined enol ethers.
Chem. Commun., 2011, 47, 8682–8684 8683
c
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We thank the National Natural Science Foundation of
China (No. 20902084), Qianjiang Talents Project of the
Science and Technology Office in Zhejiang Province
(2010R10016), and the Program for Changjiang Scholars
and Innovative Research Team in Chinese Universities
(IRT0980) for their financial support.
Notes and references
1 (a) E.-I. Negishi, Handbook of Organopalladium Chemistry for
Organic Synthesis, John Wiley & Sons, Hoboken, NJ, 2002;
(b) A. de Meijere and F. Diederich, Metal-Catalyzed Cross-
Coupling Reactions, Wiley-VCH, Weinheim, Germany, 2004, vol. 1.
2 For selected intermolecular halopalladation reactions, see:
(a) K. Kaneda, F. Kawamoto, Y. Fujiwara, T. Imanaka and
S. Teranishi, Tetrahedron Lett., 1974, 15, 1067; (b) K. Kaneda,
T. Uchiyama, Y. Fujiwara, T. Imanaka and S. Teranishi, J. Org.
Chem., 1979, 44, 55; (c) A. N. Thadani and V. H. Rawal, Org.
Lett., 2002, 4, 4317; (d) A. N. Thadani and V. H. Rawal,
Org. Lett., 2002, 4, 4321; (e) S. Ma, B. Wu and S. Zhao, Org.
Lett., 2003, 5, 4429; (f) S. Ma, B. Wu and X. Jiang, J. Org. Chem.,
2005, 70, 2588; (g) J. Huang, L. Zhou and H. Jiang, Angew.
Chem., Int. Ed., 2006, 45, 1945; (h) H. Jiang, X. Liu and
L. Zhou, Chem.–Eur. J., 2008, 14, 11305; (i) H. Jiang, C. Qiao
and W. Liu, Chem.–Eur. J., 2010, 16, 10968.
Scheme 3 Synthesis of a-allylated carbonyl compounds.
3 For intramolecular halopalladation reactions, see: (a) S. Ma and
X. Lu, J. Chem. Soc., Chem. Commun., 1990, 733; (b) S. Ma and
X. Lu, J. Org. Chem., 1991, 56, 5120; (c) S. Ma, G. Zhu and X. Lu,
Scheme 4 Proposed mechanism.
J. Org. Chem., 1993, 58, 3692; (d) J.-E. Backvall, Y. I. M. Nilsson,
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P. G. Andersson, R. G. P. Gatti and J. Wu, Tetrahedron Lett.,
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2005, 127, 6950; (f) G. Zhu and Z. Zhang, J. Org. Chem., 2005,
70, 3339; (g) Y. Liang, S. Tang, X.-D. Zhang, L.-Q. Mao,
Y.-X. Xie and J. H. Li, Org. Lett., 2006, 8, 3017; (h) S. Tang,
Q.-F. Yu, P. Peng, J.-H. Li, P. Zhong and R.-Y. Tang, Org. Lett.,
2007, 9, 3413; (i) X.-C. Huang, F. Wang, Y. Liang and J.-H. Li,
Org. Lett., 2009, 11, 1139; (j) S. Q. Ye, K. Gao, H. Zhou,
X. D. Yang and J. Wu, Chem. Commun., 2009, 5406.
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5 For a radical-mediated haloallylation of acetylenes, see: T. Kippo,
T. Fukuyama and I. Ryu, Org. Lett., 2010, 12, 4006.
substituted enol ethers,10 this protocol provides a complementary,
as well as efficient strategy to access the stereodefined multi-
substituted enol ethers.
In addition, treatment of 4a with 6 N HCl resulted in the
a-allylated ketone 5 in 95% yield (Scheme 3). More interestingly,
this method can be applied to the synthesis of a-allylated esters
via the bromoallylation–hydrolysis sequence. For instance,
a-bromoenol ether 3ag, generated in situ via the Pd-catalyzed
bromoallylation of ynol ether 1a, was hydrolyzed with the
assistance of silver nitrate to give the a-allylated ester 6a in
76% yield (unoptimized). The generality of this strategy was
preliminary demonstrated by the synthesis of functionalized
aromatic a-allylated esters 6b–6d in good yields (Scheme 3).
A plausible mechanism for this Pd-catalyzed haloallylation
of aromatic ynol ethers was illustrated in Scheme 4. The first
reasonable step is the insertion of ynol ether 1 into the Pd–Cl
bond to generate the alkenyl palladium intermediate I. Very
likely, the negative charge11 on the b-carbon of ynol ethers
may account for the regioselective b-addition of palladium,
which is similar to the reversal of regiochemistry in the Heck
reaction of electron-rich olefins.12 Then, the carbopalladation
of alkenyl palladium intermediate I with allyl halide 2 gives
an alkyl palladium intermediate II, followed by the b-Cl
elimination13 to form the a-chloroenol ether 3 and to regenerate
the palladium catalyst (Scheme 4).
6 (a) S. Ma and X. Lu, J. Org. Chem., 1993, 58, 1245;
(b) J.-E. Backvall, Y. I. M. Nilsson and R. G. P. Gatti, Organo-
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M. Shibasaki, J. Am. Chem. Soc., 1989, 111, 643; (b) M. Shindo,
T. Kita, T. Kumagai, K. Matsumoto and K. Shishido, J. Am.
Chem. Soc., 2006, 128, 1062; (c) J. R. DeBergh, K. M. Spivey and
J. M. Ready, J. Am. Chem. Soc., 2008, 130, 7828; (d) B. Bourdon,
M. Corbet, P. Fontaine, P. G. Goekjian and D. Gueyrard,
Tetrahedron Lett., 2008, 49, 747; (e) P. Lemoine and B. Daoust,
Tetrahedron Lett., 2008, 49, 6175; (f) Z. Song, L. Kui, X. Sun and
L. Li, Org. Lett., 2011, 13, 1440; (g) D. J. Winternheimer,
R. E. Shade and C. A. Merlic, Synthesis, 2010, 2497.
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(b) P. J. Stang and K. A. Roberts, J. Am. Chem. Soc., 1986,
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12 For the Heck reaction of electron-rich alkenes, see: J. Ruan and
J. Xiao, Acc. Chem. Res., 2011, 44, DOI: 10.1021/ar200053d and
references therein.
In summary, we have developed a convenient protocol for
the synthesis of (1E)-a-chloroenol ethers with excellent control
of regio- and stereochemistry under the mild conditions.
It represents the first example of halopalladation reaction
featuring the b-addition pathway. Moreover, this methodology
could be applied to the synthesis of stereodefined multi-
substituted enol ethers and a-allylated carbonyl compounds.
Further investigations on the applications of the developed
protocol are underway.
13 (a) S. A. Strazisar and P. T. Wolczanski, J. Am. Chem. Soc., 2001,
123, 4728; (b) Z. Zhang, X. Lu, Z. Xu, Q. Zhang and X. Han,
Organometallics, 2001, 20, 3724; (c) R. A. Stockland, S. R. Foley
and R. F. Jordan, J. Am. Chem. Soc., 2003, 125, 796.
c
8684 Chem. Commun., 2011, 47, 8682–8684
This journal is The Royal Society of Chemistry 2011