Efficient and reusable PdCl2(MeCN)2/CuCl 2/PEG-400 system for cyclization of alkenyl β-keto esters and amides

Article abstract of DOI:10.1021/jo0506635

PEG-400 [poly(ethylene glycol-400)] was found as an effective medium for the PdCl₂(MeCN)₂-catalyzed hydroalkylation cyclization of alkenyl β-keto esters and amides. In PEG-400, no additives such as Me ₃SiCl and Ln(OTf)₃ were required for the complete conversion of alkenyl β-keto esters. The results also snowed that CuCl ₂ could promote the reaction. In the presence of PdCl ₂(MeCN)₂, CuCl₂, and PEG-400, various alkenyl β-keto esters and amides underwent a selective cyclization reaction to give good to excellent yields of the desired six-membered-ring carbocycles. Furthermore, the PdCl₂(MeCN)₂/CuCl₂/PEG-400 system could be recycled and reused five times without any loss of catalytic activity.

Full text of DOI:10.1021/jo0506635

hoefer and co-workers4a,e first reported an effective
method for the synthesis of six-membered-ring carbo-
cycles by the palladium-catalyzed hydroalkylation intra-
molecular cyclization of â-keto esters with unactivated
Efficient and Reusable PdCl
CuCl /PEG-400 System for Cyclization of
Alkenyl â-Keto Esters and Amides
2
(MeCN)
2
/
2
Jin-Heng Li,*,† Qi-Ming Zhu, Yun Liang, and
†
†
olefins. In the presence of 10 mol % of PdCl
2
(MeCN)
2
and
Dan Yang‡
a stoichiometric amount of Me SiCl or Me
3
3
SiCl/CuCl ,
2
cyclization of various 6-alkenyl 2-keto esters was carried
out to afford the corresponding 2-substituted cyclohex-
anones in good yields. We have also reported that alkenyl
â-keto esters and amides were cyclized efficiently and
regioselectively to form six- to eight-membered-ring
Key Laboratory of Chemical Biology & Traditional Chinese
Medicine Research, College of Chemistry and Chemical
Engineering, Hunan Normal University, Changsha 410081,
China, and Department of Chemistry, The University of
Hong Kong, Pokfulam Road, Hong Kong, P. R. China
compounds in the presence of PdCl
2
(MeCN)
. In these cases, however, some additives such as
SiCl and Ln(OTf) were required to improve the
2
and Ln-
5
jhli@hunnu.edu.cn
(OTf)
Me
3
3
3
Received April 5, 2005
reaction. Besides these, the catalyst systems are very
difficult to reuse under the reported reaction conditions.
Thus, development of economically as well as environ-
mentally benign reaction conditions would be significant
due to the high price of Pd and the additives. To satisfy
both recyclability and environmental concerns, a more
facile method is to immobilize the catalyst in a liquid
phase by dissolving it into a nonvolatile and nonmixing
6
liquid such as PEG. Here, we report an efficient and
selective palladium-catalyzed cyclization of alkenyl â-keto
PEG-400 [poly(ethylene glycol-400)] was found as an effec-
tive medium for the PdCl2(MeCN)2-catalyzed hydroalkyl-
ation cyclization of alkenyl â-keto esters and amides. In
PEG-400, no additives such as Me3SiCl and Ln(OTf)3 were
required for the complete conversion of alkenyl â-keto esters.
The results also showed that CuCl2 could promote the
reaction. In the presence of PdCl2(MeCN)2, CuCl2, and PEG-
esters and amides method for the synthesis of 2-substi-
tuted cyclohexanones in the presence of PdCl (MeCN) ,
2 2
CuCl , and PEG-400 (eq 1). Furthermore, the PdCl -
2
2
(
MeCN)
2
/CuCl
2
/PEG-400 system could be recycled five
times without any loss of catalytic activity.
4
00, various alkenyl â-keto esters and amides underwent a
selective cyclization reaction to give good to excellent yields
of the desired six-membered-ring carbocycles. Furthermore,
the PdCl2(MeCN)2/CuCl2/PEG-400 system could be recycled
and reused five times without any loss of catalytic activity.
Six-membered-ring carbocycles are important struc-
tural units because of their occurrence in many biologi-
cally active natural products and their physiological
2 2
As showed in Table 1, the PdCl (MeCN) -catalyzed
cyclization reaction of methyl 3-oxooct-6-enoate (1a) was
first investigated. The results showed that PEG-400 was
an effective solvent for the reaction (entry 1). Without
any additive, substrate 1a could be consumed completely
to afford 88% yield of the corresponding cyclized product
1
properties. For these reasons, a number of efficient and
selective methods have been developed for the direct
2
synthesis of these carbocyclic compounds. One of the
most effective strategies is the transition metal-catalyzed
(2a) in the presence of 0.1 equiv of PdCl
g of PEG-400. Surprisingly, Yb(OTf) had no effected on
the reaction (entry 2). According to the suggestion of
Widenhoefer,4 the addition of CuCl
was expected to
2 2
(MeCN) and 2
cyclization reaction transformations.3 Recently, Widen-
,4
3
†
Hunan Normal University
2
‡
The University of Hong Kong.
improve the palladium cyclization reactions. Indeed,
(1) (a) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, W.;
White, C. T. In The Total Synthesis of Natural Products; Apsimon, J.
W., Ed.; Wiley: New York, 1983; Vol. 5, p 333. (b) Rigby, J. H. In
Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier
Science Publishers B.V.: Amsterdam, The Netherlands, 1988; Vol. 12,
p 233. (c) Fraga, B. M. Nat. Prod. Rep. 1996, 13, 307. (d) Dyker, G.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2223.
(4) (a) Pei, T.; Widenhoefer, R. A. J. Am. Chem. Soc. 2001, 123,
11290. (b) Pei, T.; Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc.
2003, 125, 648. (c) Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc.
2003, 125, 2056. (d) Pei, T.; Widenhoefer, R. A. Chem. Commun. 2002,
650. (e) Han, X.; Wang, X.; Pei, T.; Widenhoefer, R. A. Chem. Eur. J.
2004, 10, 6333.
(5) Yang, D.; Li, J.-H.; Gao, Q.; Yan, Y.-L. Org. Lett. 2003, 5, 2869.
(6) For selected representative papers on PEG as the media, see:
(a) Santaniello, E.; Manzocchi, A.; Sozzani, P. Tetrahedron. Lett. 1979,
20, 4581. (b) Santaniello, E.; Fiecchi, A.; Manzocchi, A.; Ferraboschi,
P. J. Org. Chem. 1983, 48, 3074. (c) Chandrasehar, S.; Narsihmulu,
Ch.; Sultana, S. S.; Reddy, N. R. K. Org. Lett. 2002, 4, 4399 and
references therein. (d) Chandrasehar, S.; Narsihmulu, Ch.; Sultana,
S. S.; Reddy, N. R. K. Chem. Commun. 2002, 1716. (e) Chandrasehar,
S.; Narsihmulu, Ch.; Saritha, B.; Sultana, S. S. Tetrahedron. Lett. 2004,
45, 5865 and references therein.
(
2) (a) Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Semmelhack, M. F., Eds.; Pergamon: Oxford, UK, 1991; Vol. 5.
b) Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
(
Pergamon: Oxford, UK, 1990. (c) Hesse, M. Ring Enlargement in
Organic Chemistry; VCH: Weinheim, Germany, 1991. (d) Renaud, P.;
Sibi, M. P., Eds. Radicals in Organic Synthesis; Wiley-VCH: Wein-
heim, Germany, 2001.
(3) (a) Negishi, E.; Cop e´ ret, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem.
Rev. 1996, 96, 365. (b) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan,
R. J. Chem. Rev. 1996, 96, 635. (c) Bates, R. W.; Satcharoen, V. Chem.
Soc. Rev. 2002, 35, 12.
1
0.1021/jo0506635 CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/20/2005
J. Org. Chem. 2005, 70, 5347-5349
5347

TABLE 1. Palladium-Catalyzed Hydroalkylation
Cyclization Reaction of Olefin 1a in PEG-400a
TABLE 2. PdCl2(MeCN)2/CuCl2-Catalyzed Cyclization of
Alkenyl 3-Keto Esters and Amides in PEG-400a
CuCl2
PdCl2(MeCN)2
(equiv)
time
(h)
yield
b
entry
1
(equiv)
(%)
0
0
0.10
0.10
0.10
0.10
0.10
0.05
0.01
0
47
48
22
4
88
85
94
90
91
96
86
0
c
2
3
4
5
6
7
0.2
1.0
2.0
1.0
1.0
1.0
4
31
44
48
d
8
a
Reaction conditions: 1a (0.5 mmol), PdCl2(MeCN)2, CuCl2, and
b
c
d
PEG-400 (4 g) at 55 °C. Isolated yield. Yb(OTf)3 (1 equiv). No
reaction was observed. >95% of 1a was recovered.
CuCl
2
could enhance the reaction rate sharply, and
equiv of CuCl gave the best results. In the presence of
.1 equiv of PdCl (MeCN) , the complete conversion of
1
0
2
2
2
substrate 1a required 47 h, whereas the presence of
.2 equiv of CuCl resulted in the complete conversion
in 22 h (entries 1 and 3). In the presence of 0.1 equiv of
PdCl (MeCN) and 1 equiv of CuCl , substrate 1a was
0
2
2
2
2
consumed completely after 4 h (entry 4). Identical results
were observed even further increasing the loadings of
CuCl
loadings of PdCl
in the presence of CuCl
In the presence of 0.01 equiv of PdCl
2
to 2 equiv (entry 5). It is noteworthy that the
(MeCN) can be decreased to 0.01 equiv
and PEG-400 (entries 6 and 7).
(MeCN) and
, 86% yield of 2a was obtained after
4 h (entry 7). No reaction was observed in the absence
(MeCN) (entry 8).
In the presence of PdCl
1.0 equiv), and PEG-400 (4 g), cyclization of various
2
2
2
2
2
1
4
equiv of CuCl
2
of PdCl
2
2
2 2 2
(MeCN) (0.10 equiv), CuCl
(
alkenyl â-keto esters 1b, 1d-h, and amides 1j were
carried out smoothly in good to excellent yields, and the
results are summarized in Table 2. The results showed
that the reaction tolerated different substituents on the
olefinic groups, and both rates and yields of the reaction
depended on the structure of the substrates. In the
a
Reaction conditions: 1 (0.5 mmol), PdCl2(MeCN)2 (0.10 equiv),
b
CuCl2 (1.0 equiv), and PEG-400 (4 g) at 55 °C. Isolated yield.
2 2 2
presence of PdCl (MeCN) (0.10 equiv), CuCl (1.0 equiv),
c
No reaction was observed. >95% of 1c was recovered. d >90% of
and PEG-400 (4 g), the desired product 2b was formed
from the olefin 1b after 4 h in 97% yield (entry 1).
Cyclization of the substrates 1e and 1f, two isomers
bearing a substituent at the terminal position of the
carbon-carbon double bond, respectively, afforded the
corresponding cyclization product 2e in good yields
1
was recovered.
7
(
-enoate (1h) afforded an exo-hydroalkylation product
2a) in 80% yield after 4 h (entry 7). In the presence of
2 2 2
PdCl (MeCN) (0.10 equiv), CuCl (1.0 equiv), and
PEG-400 (4 g), cyclization of the amide 1j was also carried
out smoothly to produce the corresponding desired prod-
uct (2j) in 94% yield (entry 9). Unfortunately, cyclization
of substrates 1c, 1i, and 1k, respectively, was not
successful (entries 2, 8, and 10).8
To check the reusability of the solvent as well as the
catalytic system, the cyclization reaction of substrate (1a)
2 2
was first evaluated in the presence of PdCl (MeCN)
(
entries 4 and 5). However, the reaction rate of the former
(E-isomer) was faster than that of the latter (Z-isomer).
Treatment of substrate 1g, an olefin having two substit-
uents at the terminal position of the carbon-carbon
double bond, with PdCl
2
2 2
(MeCN) (0.10 equiv) and CuCl
(
1
1.0 equiv) gave 96% yield of the desired product 2g after
6 h (entry 6). Surprisingly, 84% yield of a 5-exo hydro-
alkoxylation product (2d) was observed when the olefin
d bearing an internal substituent was cyclized (entry
1
5,7
(8) No cyclization reaction of substrates 1c occurred due to the
unfavorable steric hindrance, and the reaction of 1i or 1k was not
successful presumably because the olefins 1i and 1k bind less tightly
to transient metals. See: (a) Hartley, F. R. Chem. Rev. 1973, 73, 163.
(b) References 4 and 7.
3
). It is noteworthy that the reaction of methyl 3-oxooct-
(
7) Reetz, M. T.; Chatziiosidis, I.; Schwellnus K. Angew. Chem., Int.
Ed. Engl. 1981, 20, 687.
5348 J. Org. Chem., Vol. 70, No. 13, 2005

TABLE 3. Recovery and Reuse of PdCl2(MeCN)2/CuCl2/
PEG-400 for the Cyclization Reactionsa
In summary, a mild and selective PdCl
CuCl -catalyzed cyclization of alkenyl â-keto esters
protocol has been developed. In the presence of
PdCl (MeCN) , CuCl , and PEG-400, various alkenyl
â-keto esters were cyclized efficiently in good to excellent
yields. Furthermore, the PdCl (MeCN) /CuCl /PEG-400
2 2
(MeCN) /
2
2
2
2
2
2
2
system could be recycled and reused five times without
any loss of catalytic activity. Currently, further efforts
to extend the application of the system in other pal-
ladium-catalyzed transformations and investigate the
precise mechanism are underway in our laboratory.
Experimental Section
Typical Experimental Procedure for the Palladium-
Catalyzed Hydroalkylation Cyclization Reaction in PEG-
a
Reaction conditions: 1 (0.5 mmol), PdCl2(MeCN)2 (0.10 equiv),
b
400. A mixture of 1 (0.5 mmol), PdCl
CuCl (1.0 equiv) in PEG-400 (4 g) was added to a sealed tube
under N , and then the mixture was stirred at 55 °C for the
2 2
(MeCN) (0.10 equiv), and
CuCl2 (1.0 equiv), and PEG-400 (4 g) at 55 °C. Average reaction
time of five runs
2
2
desired time until complete consumption of starting material
as judged by TLC. After the mixture was extracted by dry ethyl
ether (3 × 10 mL) and evaporated, the residue was purified by
flash column chromatography (hexane/ethyl acetate) to afford
the desired coupled products 2.
(
0.10 equiv), CuCl
demonstrated in Table 3, we were gratified to observe
that the PdCl (MeCN) /CuCl /PEG-400 system could be
2
(1.0 equiv), and PEG-400 (4 g). As
2
2
2
recycled and reused five times without any loss of
activity. After initial experimentation the reaction mix-
ture was extracted with dry diethyl ether, and the PEG
2 2 2
The mixture of PdCl (MeCN) , CuCl , and PEG-400 were
solidified (cooled) and subjected to a second run of the hydro-
alkylation cyclization reaction by charging with the same
substrates (alkenyl â-keto esters and amides).
2 2 2
and PdCl (MeCN) /CuCl were then solidified and sub-
jected to a second run of the hydroalkylation reaction by
charging with the same substrates (alkenyl â-keto esters).
The results of five runs showed that they were almost
consistent in yields and rates (90%, 98%, 100%, 100%,
and 100%, respectively, for 8 h; entry 1). The cyclization
reactions of olefins 1d and 1g, respectively, could also
be recycled and reused five times without any loss of
Acknowledgment. We thank the National Natural
Science Foundation of China (No. 20202002) for finan-
cial support.
Supporting Information Available: Characterization
1
13
data and spectra ( H and C NMR) of compounds 2. This
material is available free of charge via the Internet at
http://pubs.acs.org.
activity in the presence of PdCl
2 2
(MeCN) (0.10 equiv),
CuCl (1.0 equiv), and PEG-400 (4 g) (entries 2 and 3).
2
JO0506635
J. Org. Chem, Vol. 70, No. 13, 2005 5349