Palladium-catalyzed oxidation and cyclization of carbon-carbon triple bonds in fluorous media using molecular oxygen

Article abstract of DOI:10.1055/s-0030-1259929

An intriguing, facile, and efficient oxidation and cyclization of alkynes catalyzed by Pd(OAc)₂ in a fluorous biphasic system of N,N-dimethylacetamide (DMA) and perfluorodecalin directly with molecular oxygen is described, which opens an efficient access to tetrasubstituted furans. Under the optimized conditions, intermolecular reaction between diverse alkynes provides the corresponding mixture of regioisomers with appreciable selectivity. Intramolecular oxidation and cyclization of alkynes are also successfully demonstrated. The reaction proceeds efficiently under mild conditions with atmospheric oxygen as the sole oxidant. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1259929

LETTER
1023
Palladium-Catalyzed Oxidation and Cyclization of Carbon–Carbon Triple
Bonds in Fluorous Media Using Molecular Oxygen
Oxidation and
C
yc
a
lization of
n
Carbon–Carb
m
on Triple
B
onds ei Wen,a,b Shifa Zhu,a Huanfeng Jiang,*a Azhong Wang,a Zhenwang Chena
a
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. of China
College of Science, Guangdong Ocean University, Zhanjiang 524088, P. R. of China
Fax +86(20)87112906; E-mail: jianghf@scut.edu.cn
b
Received 16 November 2010
Dedicated to Professor Xiyan Lu and Professor Lixin Dai
oxygen as the oxidant to afford tetrasubstituted furans.6
However, the method has problems including drastic reac-
tion conditions, narrow substrate scope, and low yield.
Therefore, development of a mild and practical synthetic
Abstract: An intriguing, facile, and efficient oxidation and cycliza-
tion of alkynes catalyzed by Pd(OAc)2 in a fluorous biphasic system
of N,N-dimethylacetamide (DMA) and perfluorodecalin directly
with molecular oxygen is described, which opens an efficient access
to tetrasubstituted furans. Under the optimized conditions, intermo- method is more attractive.
lecular reaction between diverse alkynes provides the correspond-
Perfluorinated hydrocarbons, which can fully solubilize a
ing mixture of regioisomers with appreciable selectivity.
Intramolecular oxidation and cyclization of alkynes are also suc-
cessfully demonstrated. The reaction proceeds efficiently under
mild conditions with atmospheric oxygen as the sole oxidant.
range of gases,7 were used firstly for synthetic applica-
tions by Horvath and Rabai. They showed that perfluori-
nated hydrocarbons are ideal solvents for organic
reactions, in which gases serve as one reactant, particular-
ly suited for oxidation reactions.8 Indeed, a variety of
common organic reactions have achieved in fluorous me-
dia.9
Key words: perfluorodecalin, molecular oxygen, alkynes, palladi-
um-catalyzed, oxidation
Functionalized furans play important roles in organic
chemistry not only due to their presence as key structural
units in many natural products and important pharmaceu-
ticals,1 but they can also serve as important intermediates
for many organic transformations.2 Therefore, the synthe-
ses of polysubstituted furans continue to attract the inter-
est of many synthetic chemists.3
In this manuscript, we report on using fluorous solvents
which can be potentially reused for further reaction runs
as medium to synthesize tetrasubstituted furans by
Pd(OAc)2-catalyzed oxidation and inter- and intramolec-
ular alkyne–alkyne cyclization with atmospheric oxygen
as the sole oxidant under very mild conditions. Reaction
of diverse alkynes is also successfully demonstrated. This
should significantly expand the range of suitable starting
materials for the synthesis of tetrasubstituted furans.
Classical methods for the preparation of substituted furans
have been based on direct functionalization of existing
furans or cyclization of acyclic substrates.4 Among differ-
ent protocols for achieving this goal, transition-metal-
catalyzed cycloisomerization of unsaturated acyclic pre-
cursors to prepare multiple substituted furans has attracted
much attention. However, these known synthetic methods
have several drawbacks, for example, insufficient yields
of the desired compounds, harsh conditions, and/or the ab-
sence of an efficient and general procedure for the prepa-
ration of the rather advanced starting materials. There is
still a need for new improved routes, which should be suit-
able for constructing molecular materials and avoid the
use of stoichiometric reagents.
Catalyzed oxidation and cyclization of 1,2-diphenyl-
ethyne in perfluorodecalin (C10F18, cis and trans mixture)
was selected as a model reaction for studying the effect of
co-solvent and Lewis acid. As shown in Table 1, the reac-
tion did not proceed without Lewis acid (Table 1, entry 1).
To our delight, we found that the reaction performed with
addition of ZnCl2 (Table 1, entry 2). The reaction showed
strong co-solvent dependence. Among the co-solvents
used, DMF, 1,4-dioxane, and DMA were proved appro-
priate (Table 1, entries 2–7). A variety of Lewis acids
were tried (Table 1, entries 8–10), and the results showed
that when ZnCl2 was employed the reaction could afford
2a in good yields. The lower product yield of 40% was ob-
tained when decreasing the catalyst amount from 10
mol% to 2 mol% (Table 1, entry 11). Moreover, the yield
of tetrasubstituted furans decreased dramatically in the
absence of perfluorodecalin after 24 hours (Table 1, entry
12). It is noteworthy that the reaction proceeded badly un-
der air atmosphere (Table 1, entry 13). The optimized
reaction conditions are as following: 1a (1.0 mmol),
Pd(OAc)2 (10 mol%) with Lewis acid (20 mol%) and co-
solvent (0.5 mL), perfluorodecalin(C10F18, cis and trans
mixture, 0.5 mL) at 60 °C for 24 hours (Table 1, entry 7).
Palladium-mediated organic transformations continue to
be a fascinating area in organic synthesis as well as orga-
nometallic chemistry due to their versatility and ability to
give unexpected outcomes.5 In a preliminary communica-
tion, we have reported the utility of a catalytic amount
Pd(OAc)2, and Zn(OTf)2 efficiently catalyzed the oxida-
tion and cyclization of aromatic alkynes with molecular
SYNLETT 2011, No. 7, pp 1023–1027
x
x.
x
x.
2
0
1
1
Advanced online publication: 29.03.2011
DOI: 10.1055/s-0030-1259929; Art ID: W34010ST
© Georg Thieme Verlag Stuttgart · New York

1024
Y. Wen et al.
LETTER
Table 1 Optimization of Reaction Conditions for the Synthesis of Tetrasubstituted Furansa
O
Pd(OAc)2, Lewis acid
perfluorodecalin, co-solvent
2
O2 (1atm), 60 °C
1a
2a
Entry
1
Lewis acid
–
Co-solvent
DMA
Yield (%)b
0
2
ZnCl2
MeCN
EtOH
3
3
ZnCl2
14
4
ZnCl2
DMF
87
5
ZnCl2
1,4-dioxane
DMSO
DMA
81
6
ZnCl2
57
7
ZnCl2
94 (90)
trace
5
8
ZnCl2·H2O
Zn(OTf)2
CuCl2
ZnCl2
DMA
9
DMA
10
11c
12d
13e
DMA
0
DMA
40
ZnCl2
DMA
8
ZnCl2
DMA
trace
a Reaction conditions: 1,2-Diphenylacetylene (1.0 mmol), Pd(OAc)2 (10 mol%), Lewis acid (20 mol%), co-solvent (0.5 mL), and perfluoro-
decalin (C10F18, cis and trans mixture, 0.5 mL), 60 °C, O2 (1 atm), 24 h.
b Determined by GC. Number in parentheses was isolated yield.
c Pd(OAc)2 (2 mol%).
d DMA (1.0 mL), perfluorodecalin (0 mL).
e Air (1 atm).
With the optimized reaction conditions in hand (Table 1,
entry 7), we began to explore the scope and limitations of
this method. As shown in Table 2, this transformation was
highly efficient for a broad scope of substrates, wherein
various functional groups, including halide, methoxy,
alkyl, and trifluoromethyl could be tolerated, and product
2g was structurally characterized by X-ray diffraction
measurement (Figure 1). Suitable alkyne substrates were
easily prepared by Sonogashira reaction, and the oxida-
tion cyclization reaction proceeded smoothly to give the
tetrasubstituted furans 2a–k in good to excellent yields.
It was found that alkynes containing a substituent at the 2-
position generally resulted in lower yields than alkynes
containing substituent at the 3- or 4-position (Table 2, en-
tries 8–10). This may be attributed to steric effects. Other-
wise, 1,2-di-p-tolylethyne (1b), 1,2-bis(4-butylphenyl)-
ethyne (1c), 1,2-bis(4-methoxyphenyl)ethyne (1d), and
1,2-di-m-tolylethyne (1e) possessing electron-donating
groups on the aromatic ring afforded the product 2b, 2c,
Figure 1 X-ray crystal structure of compound 2g
2d, and 2e in 90%, 89%, 80%, and 65% isolated yields, re-
spectively (Table 2, entries 1–4). In comparison, reaction
of 1,2-bis(3-chlorophenyl)ethyne (1f), 1,2-bis[4-(trifluo-
Synlett 2011, No. 7, 1023–1027 © Thieme Stuttgart · New York

LETTER
Oxidation and Cyclization of Carbon–Carbon Triple Bonds
1025
romethyl)phenyl]ethyne (1g), and 1,2-bis(4-bromophe- Next, the practical utility of this oxidation and cyclization
nyl)ethyne (1h) substituted with electron-withdrawing process between diverse alkynes under typical conditions
groups took place in higher yield to give products 2f, 2g, was evaluated. The reactions of 1,2-diphenylethyne (1a),
and 2h in 74%, 95%, and 86% (Table 2, entries 5–7). 1,2-bis(4-(trifluoromethyl)phen yl)ethyne (1g), or 1,2-di-
Noteworthy, the tetrasubstituted furan formation that tol- p-tolylethyne (1b) with 1,2-bis(4-butylphenyl)ethyne (1c)
erates aryl bromides offers potential for further function- were investigated briefly and resulted in statistical distri-
alization of furans by, for example, catalytic cross- bution of symmetric tetrasubstituted furans along with the
coupling reactions.
dissymmetric product (Scheme 1).
R1
R2
R1
R2
R1
Pd(OAc)2, ZnCl2
perfluorodecalin,DMA
R1
+
R2
R2
O
O
O
O2 (1atm), 60 °C
R1
+
+
R2
R1
R1
R2
R1
R2
R2
3ac, 3bc, 3gc
1a: R1 = H
1c: R2 = n-Bu
2a, 2b, 2g
2c
1b: R1 = Me
1g: R1 = CF3
n-Bu
n-Bu
n-Bu
O
O
O
n-Bu
n-Bu
n-Bu
3ac
50%
2a
26%
2c
24%
n-Bu
n-Bu
n-Bu
O
O
O
n-Bu
n-Bu
n-Bu
2b
28%
2c
20%
3bc
52%
F3C
n-Bu
n-Bu
n-Bu
CF3
CF3
O
O
O
F3C
n-Bu
CF3
n-Bu
n-Bu
CF3
3gc
54%
2g
29%
2c
17%
Scheme 1 Pd(OAc)2/ZnCl2-catalyzed oxidation cyclization of diverse alkynes to afford tetrasubstituted furans. Reactions were carried out
using diverse alkynes (0.5 + 0.5 mmol), Pd(OAc)2 (10 mol%), Lewis acid (20 mol%), DMA (0.5 mL), and perfluorodecalin (C10F18, cis and
trans mixture, 0.5 mL), 60 °C, O2 (1 atm), 24 h. Isolated yields are given.
Synlett 2011, No. 7, 1023–1027 © Thieme Stuttgart · New York

1026
Y. Wen et al.
LETTER
Table 2 Pd(OAc)2/ZnCl2-Catalyzed Oxidation Cyclization of Vari-
ous Alkynes to Afford Tetrasubstituted Furansa
O
Pd(OAc)2 (10 mol%)
ZnCl2 (20 mol%)
Pd(OAc)2, ZnCl2
perfluorodecalin, DMA
O
Ar
Ar
perfluorodecalin, DMA
O2 (1atm), 60 °C
Ar
Ar
2
O2 (1atm), 60 °C
1
Ar
Ar
2l, 32%
2
1,7-diphenylhepta-1,6-diyne
Scheme 2 Pd(OAc)2/ZnCl2-catalyzed oxidation–cyclization of in-
ternal alkynes
Entry
1
Ar
Product
Yield (%)b
2b
2c
2d
90
In summary, we have developed a highly efficient method
for palladium-catalyzed oxidation–cyclization reaction of
alkynes to synthesize tetrasubstituted furans with an
atmospheric oxygen as the sole oxidant in a fluorous bi-
phasic system of N,N-dimethylacetamide and perfluoro-
decalin at 60 °C (Scheme 2). The presented results clearly
demonstrate that Pd(II) acted as a one-pot catalyst to cat-
alyze the oxidation of alkynes followed by an efficient cy-
clization reaction, which resulted in a direct conversion of
alkynes into tetrasubstituted furans. It is also indicated
that not only intermolecular but also intramolecular
alkyne–alkyne coupling, oxidation, and cyclization can
complete under similar reaction conditions. The utiliza-
tion of perfluorocarbon should significantly expand the
range of suitable starting materials for the oxidation of
alkynes. As the reaction tolerates aryl halides, it could po-
tentially provide access to a variety of molecular materi-
als, as well as mixed arylfuran polymers from aromatic
diynes. This novel oxidation methodology should find
widespread use in organic synthesis. Further synthetic ap-
plications and studies of the reaction mechanism are in
progress.
1b
n-Bu
1c
2
3
89
80
MeO
1d
4
5
2e
2f
65
74
1e
Cl
1f
F3C
1g
Br
6
7
8
2g
2h
2i
95
86
83
1h
F
Typical Procedure for the Preparation of the Tetrasubstituted
Furans
1i
F
Alkyne (1 mmol), Pd(OAc)2 (10 mol%), and ZnCl2 (20 mol%) were
added to an oven-dried Schlenck tube under air. The septum-sealed
tube was evacuated and refilled with O2 thrice. DMA (0.5 mL) and
perfluorodecalin (0.5 mL) were added via syringe. The reaction
mixture was heated in an oil bath at 60 °C for 24 h. After the reac-
tion completed, the product was obtained by silica gel chromatog-
raphy with light PE–CH2Cl2 as eluent.
9
2j
69
46
1j
10
2k
F
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
1k
a Reactions were carried out using alkyne (1 mmol), Pd(OAc)2 (10
mol%), Lewis acid (20 mol%), DMA (0.5 mL), and perfluorodecalin
(C10F18, cis and trans mixture, 0.5 mL), 60 °C, O2 (1 atm), 24 h.
b Isolated yields.
Acknowledgment
The authors thank the National Natural Science Foundation of Chi-
na (Grants 20332030, 20572027, 20625205 and 20772034), Natio-
nal Basic Research Program of China (973 Program) (No.
2011CB808600), the Doctoral Fund of the Ministry of Education of
China (20090172110014), and Guangdong Natural Science Found-
ation (No. 10351064101000000) for financial support
To further extend the scope of the reaction, we have ex-
plored the utility of internal alkynes. Unfortunately, the
yields were low under the optimized conditions.
Synlett 2011, No. 7, 1023–1027 © Thieme Stuttgart · New York

LETTER
Oxidation and Cyclization of Carbon–Carbon Triple Bonds
1027
Catal. 2010, 352, 143. (i) Zhang, X.; Lu, Z.; Fu, C.; Ma, S.
J. Org. Chem. 2010, 75, 2589. (j) Brown, R. C. D. Angew.
Chem. Int. Ed. 2005, 44, 850. (k) Cacchi, S. J. Organomet.
Chem. 1999, 576, 42. (l) Keay, B. A. Chem. Soc. Rev. 1999,
28, 209.
References
(1) (a) Mortensen, D. J.; Rodriguez, A. L.; Carlson, K. E.; Sun,
J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med.
Chem. 2001, 44, 3838. (b) Francesconi, I.; Wilson, W. D.;
Tanious, F. A.; Hall, J. E.; Bender, B. C.; Tidwell, R. R.;
McCurdy, D.; Boykin, D. W. J. Med. Chem. 1999, 42, 2260.
(c) Rahmathullah, S. M.; Hall, J. E.; Bender, B. C.;
(4) (a) Nakano, M.; Tsurugi, H.; Satoh, T.; Miura, M. Org. Lett.
2008, 10, 1851. (b) Brown, R. C. D. Angew. Chem. Int. Ed.
2005, 44, 850. (c) Kirsch, S. F. Org. Biomol. Chem. 2006, 4,
2076. (d) Kawai, H.; Oi, S.; Inoue, Y. Heterocycles 2006,
67, 101. (e) Li, Y.; Yu, Z. J. Org. Chem. 2009, 74, 8904.
(f) Xiao, Y.; Zhang, J. L. Chem. Commun. 2010, 752.
(g) Wang, T.; Zhang, J. Dalton Trans. 2010, 39, 4270.
(h) Dudnik, A. S.; Gevorgyan, V. Angew. Chem. Int. Ed.
2007, 46, 5195. (i) Fukuda, Y.; Shiragami, H.; Utimoto, K.;
Nozaki, H. J. Org. Chem. 1991, 56, 5816. (j) Sniady, A.;
Wheeler, K. A.; Dembinski, R. Org. Lett. 2005, 7, 1769.
(k) Gabriele, B.; Salerno, G.; Lauria, E. J. Org. Chem. 1999,
64, 7687. (l) Seiller, B.; Bruneau, C.; Dixneuf, P. H.
Tetrahedron 1995, 51, 13089. (m) Liu, Y.; Song, F.; Song,
Z.; Liu, M.; Yan, B. Org. Lett. 2005, 7, 5409.
McCurdy, D. R.; Tidwell, R. R.; Boykin, D. W. J. Med.
Chem. 1999, 42, 3994. (d) Mullican, M. D.; Sorenson, R. J.;
Connor, D. T.; Thueson, D. O.; Kennedy, J. A.; Conroy,
M. C. J. Med. Chem. 1991, 34, 2186. (e) Flynn, B. L.;
Hamel, E.; Jung, M. K. J. Med. Chem. 2002, 45, 2670.
(f) Giardina, D.; Crucianelli, M.; Romanelli, R.; Leonardi,
A.; Poggesi, E.; Melchiorre, C. J. Med. Chem. 1996, 39,
4602. (g) Hopkins, K. T.; Wilson, W. D.; Bender, B. C.;
McCurdy, D. R.; Hall, J. E.; Tidwell, R. R.; Kumar, A.;
Bajic, M.; Boykin, D. W. J. Med. Chem. 1998, 41, 3872.
(h) Bolognesi, M. L.; Budriesi, R.; Chiarini, A.; Poggesi, E.;
Leonardi, A.; Melchiorre, C. J. Med. Chem. 1998, 41, 4844.
(i) Cacchi, S. J. Organomet. Chem. 1999, 576, 42. (j) Hou,
X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.;
Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998, 54, 1955.
(2) (a) Nishino, H.; Kajikawa, S.; Hamada, Y.; Kurosawa, K.
Tetrahedron Lett. 1995, 36, 5753. (b) Lee, H.-K.; Chan,
K.-F.; Hui, C.-W.; Yim, H.-K.; Wu, X.-W.; Wong, H. N. C.
Pure Appl. Chem. 2005, 77, 139. (c) Dean, F. M. Adv.
Heterocycl. Chem. 1982, 30, 167. (d) Lipshutz, B. H. Chem.
Rev. 1986, 86, 795. (e) Brown, T. H.; Armitage, M. A.;
Blakemore, R. C.; Blurton, P.; Durant, G. J.; Ganellin, C. R.;
Ife, R. J.; Parsons, M. E.; Rawlings, D. A.; Slingsby, B. P.
Eur. J. Med. Chem. 1990, 217.
(3) (a) Onitsuka, S.; Nishino, H.; Kurosawa, K. Tetrahedron
Lett. 2000, 41, 3149. (b) Dudnik, A. S.; Sromek, A. W.;
Rubina, M.; Kim, J. T.; Kel’in, A. V.; Gevorgyan, V. J. Am.
Chem. Soc. 2008, 130, 1440. (c) Schwier, T.; Sromek,
A. W.; Yap, D. M. L.; Chernyak, D.; Gevorgyan, V. J. Am.
Chem. Soc. 2007, 129, 9868. (d) Peng, L. L.; Zhang, X.; Ma,
M.; Wang, J. B. Angew. Chem. Int. Ed. 2007, 46, 1905.
(e) Sromek, A. W.; Rubina, M.; Gevorgyan, V. J. Am. Chem.
Soc. 2005, 127, 10500. (f) Xia, Y. Z.; Dudnik, A. S.;
Gevorgyan, V.; Li, Y. H. J. Am. Chem. Soc. 2008, 130,
6940. (g) Feng, X.; Tan, Z.; Chen, D.; Shen, Y.; Guo, C.;
Xiang, J.; Zhu, C. Tetrahedron Lett. 2008, 49, 4110.
(h) Cao, H.; Jiang, H.; Mai, R.; Zhu, S.; Qia, C. Adv. Synth.
(5) (a) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644.
(b) Beccalli, E. M.; Broggini, G.; Martinelli, M.;
Sottocornola, S. Chem. Rev. 2007, 107, 5318. (c) Chen, X.;
Engle, K. M.; Wang, D.; Yu, J. Angew. Chem. Int. Ed. 2009,
48, 5094. (d) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010,
110, 1147.
(6) Wang, A.; Jiang, H.; Xu, Q. Synlett 2009, 929.
(7) Sharts, C. M.; Reese, H. R. J. Fluorine Chem. 1978, 11, 637.
(8) (a) Horváth, I. T.; Rábai, J. Science 1994, 266, 72.
(b) DiMagno, S. G.; Dussault, P. H.; Schultz, J. A. J. Am.
Chem. Soc. 1996, 118, 5312.
(9) (a) Lu, N.; Lin, Y. Tetrahedron Lett. 2007, 48, 8823.
(b) Betzemeier, B.; Lhermitte, F.; Knochel, P. Tetrahedron
Lett. 1998, 39, 6667. (c) Hope, E. G.; Kemmitt, R. D. W.;
Paige, D. R.; Stuart, A. M. J. Fluorine Chem. 1999, 99, 197.
(d) Shen, M.; Cai, C.; Yi, W. J. Fluorine Chem. 2007, 128,
1421. (e) Hao, X.; Yamazaki, O.; Yoshida, A.; Nishikido, J.
Green Chem. 2003, 5, 524. (f) Colonna, S.; Gaggero, N.;
Montanari, F.; Pozzi, G.; Quici, S. Eur. J. Org. Chem. 2001,
181. (g) Schneider, S.; Bannwarth, W. Angew. Chem. Int.
Ed. 2000, 39, 4142. (h) Tesevic, V.; Gladysz, J. A. J. Org.
Chem. 2006, 71, 7433. (i) Contel, M.; Villuendas, P. V.;
Gallardo, J. F.; Alonso, P. J.; Vincent, J. M.; Fish, R. H.
Inorg. Chem. 2005, 44, 9771. (j) Curran, D. P.; Hadida, S.
J. Am. Chem. Soc. 1996, 118, 2531.
Synlett 2011, No. 7, 1023–1027 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.