Palladacycle-catalyzed reaction of bicyclic alkenes with terminal ynones: Regiospecific synthesis of polysubstituted furans

Article abstract of DOI:10.1021/ol302586m

A new synthetic strategy to access polysubstituted furans regiospecifically has been developed using simple bicyclic alkenes and terminal ynones as starting materials with palladacycles as unique active catalysts. A rational mechanism has also been proposed. This reaction features mild reaction conditions, easily available starting materials and palladacycle catalysts, a wide substrate scope, and high regiospecificity.

Full text of DOI:10.1021/ol302586m

ORGANIC
LETTERS
2012
Vol. 14, No. 22
5756–5759
Palladacycle-Catalyzed Reaction
of Bicyclic Alkenes with Terminal
Ynones: Regiospecific Synthesis
of Polysubstituted Furans
Guang-Cun Ge,† Dong-Liang Mo,† Chang-Hua Ding,† Li-Xin Dai,† and Xue-Long Hou*,†,‡
State Key Laboratory of Organometallic Chemistry, Shanghai-Hong Kong Joint
Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences 345 Ling Ling Road, Shanghai 200032, China
xlhou@sioc.ac.cn
Received September 30, 2012
ABSTRACT
A new synthetic strategy to access polysubstituted furans regiospecifically has been developed using simple bicyclic alkenes and terminal
ynones as starting materials with palladacycles as unique active catalysts. A rational mechanism has also been proposed. This reaction features
mild reaction conditions, easily available starting materials and palladacycle catalysts, a wide substrate scope, and high regiospecificity.
The furan ring as a key structural unit has been found in
a variety of natural products and important pharma-
ceuticals.1 Polysubstituted furans have also served as
versatile building blocks in organic synthesis. A variety
ofinter- and intramolecular strategieshavebeen developed
to synthesize furan rings.2 Among them, alkyne- or allene-
containing derivatives with other functional groups are the
most used starting materials in the metal-catalyzed furan
synthesis.2,3 However, their preparation requires multistep
syntheses and/or possesses troublesome operations. Devel-
opment of new and efficient synthetic protocols of furans
using readily available and cheap chemicals as reactants
is a great challenge. On the other hand, palladacycles are
(2) For some recent examples: (a) Lenden, P.; Entwistle, D. A.; Willis,
M. C. Angew. Chem., Int. Ed. 2011, 50, 10657. (b) Chen, Z.; Huang, G.;
Jiang, H.; Huang, H.; Pan, X. J. Org. Chem. 2011, 76, 1134. (c) Dudnik,
A. S.; Xia, Y.; Li, Y.; Gevorgyan, V. J. Am. Chem. Soc. 2010, 132, 7645. (d)
Kao, T.-T.; Syu, S.-e.; Jhang, Y.-W.; Lin, W. Org. Lett. 2010, 12, 3066. (e)
€
Kramer, S.; Madsen, J. L. H.; Rottlander, M.; Skrydstrup, T. Org. Lett.
2010, 12, 2758. (f) Chen, J.; Ma, S. Chem.;Asian J. 2010, 5, 2415. (g) Zhang,
M.; Jiang, H.-F.; Neumann, H.; Beller, M.; Dixneuf, P. H. Angew. Chem.,
Int. Ed. 2009, 48, 1681. (h) Pan, Y.-M.;Zhao, S.-Y.; Ji, W.-H.;Zhan, Z.-P. J.
Comb. Chem. 2009, 11, 103. (i) Aponick, A.; Li, C.-Y.; Malinge, J.; Marques,
E. F. Org. Lett. 2009, 11, 4624. (j) Blanc, A.; Tenbrink, K.; Weibel, J.-M.;
Pale, P. J. Org. Chem. 2009, 74, 4360. (k) Liu, F.; Yu, Y.; Zhang, J. Angew.
Chem., Int. Ed. 2009, 48, 5505. (l) Zhang, G.; Huang, X.; Li, G.; Zhang, L.
J. Am. Chem. Soc. 2008, 130, 1814. (m) Xiao, Y.; Zhang, J. Angew. Chem.,
Int. Ed. 2008, 47, 1903. (n) Shibata, Y.; Noguchi, K.; Hirano, M.; Tanaka,
K. Org. Lett. 2008, 10, 2825. (o) Barluenga, J.; Riesgo, L.; Vicente, R.;
† State Key Laboratory of Organometallic Chemistry.
‡ Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis.
(1) For some reviews: (a) Hou, X. L.; Peng, X. S.; Yeung, K. S.;
Wong, H. N. C. Furans. In Sciences of Synthesis, Knowledge Updates
2011/2; Carreira, E. M., Drabowicz, J., Fuerstner, A., Krause, N., Moloney,
M. G., Vol. Eds.; Thieme: Stuttgart, 2011; p 261. (b) Balme, G.; Bouyssi, D.;
Monteiro, N. Heterocycles 2007, 73, 87. (c) Patil, N. T.; Yamamoto, Y.
ARKIVOC 2007, 121. (d) Kirsch, S. F. Org. Biomol. Chem. 2006, 4, 2076.
(e) Brown, R. C. D. Angew. Chem., Int. Ed. 2005, 44, 850. (f) 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.
ꢀ
ꢀ
Lopez, L. A.; Tomas, M. J. Am. Chem. Soc. 2008, 130, 13528. (p)
ꢀ
Aurrecoechea, J. M.; Durana, A.; Perez, E. J. Org. Chem. 2008, 73, 3650.
(q) Peng, L.; Zhang, X.; Ma, M.; Wang, J. Angew. Chem., Int. Ed. 2007, 46,
1905. (r) Arimitsu, S.; Hammond, G. B. J. Org. Chem. 2007, 72, 8559. (s)
Zhou, C.-Y.; Chan, P. W. H.; Che, C.-M. Org. Lett. 2006, 8, 325. (t) Zhang,
J.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2006, 45, 6704. (u) Sromek, A. W.;
Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc. 2005, 127, 10500. (v) Sniady,
A.; Wheeler, K. A.; Dembinski, R. Org. Lett. 2005, 7, 1769.
r
10.1021/ol302586m
Published on Web 11/12/2012
2012 American Chemical Society

easily available organometallics with extra stability toward
air and moisture, versatile frameworks, and high catalytic
activity and represent an important class of catalysts in
organic synthesis.4 Many advantages have been shown by
using palladacycles as catalysts, and high turnover num-
bers have been achieved. Mechanistic studies showed,
however, that they served as catalyst precursors very often,
producing nanoparticles as the real catalyst. Only a few
reports have appeared to date that used palladacycles as
transition metal catalysts.5,6 Exploration of the applica-
tions of palladacycles as real transition metal catalysts,
especially in CꢀC bond formation, is still in high demand.
As part of a program aimed at developing palladacycles
as real transition-metal catalysts, we have studied the
reaction of oxabicyclic alkenes with different reagents by
using palladacycles as catalysts.6 In this communication,
we report the reaction of bicyclic alkenes with terminal
ynones7,8 to afford trisubstituted furans regiospecifically,
in which a palladacycle serves as a unique and efficient
catalyst. Mechanistic investigations to rationalize the ex-
perimental observations are also demonstrated.
Figure 1. Palladacycles with different scaffolds and donor atoms.
Pd(OAc)2, Pd(OAc)2/PPh3, Pd2(dba)3, Pd(PPh3)2Cl2, and
Pd(OAc)2/diphenylphosphine oxide,8f were used as catalysts.
To have a better understanding of the reaction, the
influence of the parameters on the reaction was investi-
gated. It showedthat both the structure scaffold and donor
atom of the palladacycles have a great impact on the
reaction (Figure 1, Table 1). The palladacycle P2,9 an
analogue of palladacycle P1,10 gave furan 3a in 10% yield,
while a 62% yield of 3a was provided using palladacycleP1
(entry 2 vs 1). The palladacycle P3 based on a naphthalene
scaffold gave a slightly higher yield than P1 (entry 3 vs 1).
The change of OAc in palladacycle P311 to acac in pallada-
cycle P411 resulted in a similar yield of furan 3a (entry 4
vs 3), while the use of palladacycles P5 and P612 containing
sp3 carbonꢀpalladium bonds provided furan 3a in 34%
yield (entries 5 and 6). Palladacycles P710 and P810 with a
nitrogen donor atom showed low catalytic activity in the
reaction, with a trace amount of product 3a being observed
(entries 7 and 8). With palladacycle P3 as the catalyst,
the effect of temperature on the reaction was evaluated.
Raising the temperature did not change the yield of furan
3a (entry 9 vs 3). In contrast, an increase of the yield of
furan 3a to 76% was observed by lowering the temperature
to rt (entry 10 vs 3). Lowering the temperature to 0 °C did
not improve the yield further (entry 11).
It was observed that the reaction gave furan 3a only in
54% yield in the absence of acid using palladacycle P3
as the catalyst at rt. The addition of bases such as Et3N
and Cs2CO3 made the reaction sluggish, providing a trace
amount of furan 3a, although ynone 2a was consumed
completely. These results indicate the importance of the
presence of acid. Thus, the effect of acid as additives on the
reaction was investigated (Table 2). Stronger acids such
as CF3CO2H and 2,4,6-F3C6H2CO2H have a deleterious
impact on the reaction, with only a trace amount of
furan 3a being observed (entries 1 and 2), while the other
We observed the formation of the furan ring in the
reaction of 7-oxabenzonorbornadiene (1a) with a terminal
ynone (2a) in the presence of palladacycle P1 as a catalyst
when we studied the reaction of alkynes with oxabicyclic
alkenes6b,c (entry 1, Table 1). Control experimentsrevealed
that the presence of a palladacycle is crucial because no
reaction took place or very low yields (<10%) were
achieved if some common palladium species, such as
(3) For an intramolecular Wacker-type oxidation of simple alkene to
form furan: (a) Han, X.; Widenhoefer, R. A. J. Org. Chem. 2004, 69,
1738. For oxidative addition of the sp CꢀH to palladium: (b) Trost,
€
B. M.; Sorum, M. K.; Chan, C.; Harms, A. E.; Ruhter, G. J. Am. Chem.
Soc. 1997, 119, 698. (c) Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc.
2001, 123, 11107. (d) Yang, C.-L.; Nolan, S. P. J. Org. Chem. 2002, 67,
591. (e) Jahier, C.; Zatolochnaya, O. V.; Zvyagintsev, N. V.; Ananikov,
V. P.; Gevorgyan, V. Org. Lett. 2012, 14, 2846.
(4) For some reviews: (a) Dupont, J.; Consorti, C. S.; Spencer, J.
Chem. Rev. 2005, 105, 2527. (b) Farina, V. Adv. Synth. Catal. 2004, 346,
1553. (c) Bedford, R. B. Chem. Commun. 2003, 1787. (d) van der Boom,
M. E.; Milstein, D. Chem. Rev. 2003, 103, 1759. (e) Herrmann, W. A.;
€
Brobmer, C.; Ofele, K.; Reisinger, C.-P.; Priermeier, T.; Beller, M.;
Fischer, H. Angew. Chem., Int. Ed. Engl. 1995, 34, 1844. (f) d’Orlye, F.;
Jutand, A. Tetrahedron 2005, 61, 9670.
(5) (a) Tenaglia, A.; Jeune, K. L.; Giordano, L.; Buono, G. Org. Lett.
2011, 13, 636. (b) He, P.; Lu, Y.; Dong, C. G.; Hu, Q. S. Org. Lett. 2007,
9, 343. (c) Suzuma, Y.; Yamamoto, T.; Ohta, T.; Ito, Y. Chem. Lett.
2007, 36, 470. (d) Tenaglia, A.; Giordano, L.; Buono, G. Org. Lett. 2006,
8, 4315.
(6) (a) Zhang, T.-K.; Yuan, K.; Hou, X.-L. J. Organomet. Chem.
2007, 692, 1912. (b) Zhang, T.-K.; Mo, D.-L.; Hou, X.-L.; Dai, L.-X.
Org. Lett. 2008, 10, 3689. (c) Huang, X.-J.; Mo, D.-L.; Ding, C.-H.;
Hou, X.-L. Synlett 2011, 943.
(7) For examples of reactions of ynones with diazo ester or aldehydes
to afford furans: (a) Zhao, L.-B.; Guan, Z.-H.; Han, Y.; Xie, Y.-X.; He,
S.; Liang, Y.-M. J. Org. Chem. 2007, 72, 10276. (b) Takai, P.; Morita, R.;
Sakamoto, S. Synlett 2001, 1614.
(8) For examples of transition-metal-catalyzed reactions of alkynes
with bicyclic alkenes: (a) Fan, B. M.; Li, X. J.; Peng, F. Z.; Zhang, H. B.;
Chan, A. S. C.; Shao, Z. H. Org. Lett. 2010, 12, 304. (b) Nishimura, T.;
Tsurumaki, E.; Kawamoto, T.; Guo, X. X.; Hayashi, T. Org. Lett. 2008,
10, 4057. (c) Rayabarapu, D. K.; Chiou, C.-F.; Cheng, C.-H. Org. Lett.
2002, 4, 1679. (d) Huang, D.-J.; Rayabarapu, D. K.; Li, L.-P.; Sambaiah,
T.; Cheng, C.-H. Chem.;Eur. J. 2000, 6, 3706. (e) Prdigon, O.; Tenaglia,
A.; Buono, G. J. Org. Chem. 1995, 60, 1868. (f) Bigeaault, J.; Giordano,
L.; Buono, G. Angew. Chem., Int. Ed. 2005, 44, 4753. (g) Bigeaault, J.;
Giordano, L.; de Riggi, I.; Gimbert, Y.; Buono, G. Org. Lett. 2007, 9,
3567.
(9) Zim, D.; Buchwald, S. L. Org. Lett. 2003, 5, 2413.
(10) Zhang, T. K.; Mo, D. L.; Dai, L. X.; Hou, X. L. Org. Lett. 2008,
10, 5337.
(11) Frey, G. D.; Reisinger, C. P.; Herdtweck, E.; Herrmann, W. A.
J. Organomet. Chem. 2005, 690, 3193.
€
(12) (a) Herrmann, W. A.; Brobmer, C.; Ofele, K.; Reisinger, C.-P.;
Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem., Int. Ed. Engl. 1995,
ꢀ
34, 1844. (b) d’Orlye, F.; Jutand, A. Tetrahedron 2005, 61, 9670.
Org. Lett., Vol. 14, No. 22, 2012
5757

Table 1. Screening of Palladacycles and Temperature for the
Reaction of Oxabicyclic Alkene 1a with Terminal Ynone 2aa
Table 3. Substrate Scope for Palladacycle P3-Catalyzed
Reaction of Bicyclic Alkenes 1 with Terminal Ynones 2a
entry
palladacycle
temp (°C)
3a (%)b
1
P1
P2
P3
P4
P5
P6
P7
P8
P3
P3
P3
50
50
50
50
50
50
50
50
80
rt
62
2
10c
64
3
4
61
5
34
6
34
7
tracec
tracec
66
8
9
10
11
76
0
71
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), ClCH2CH2Cl
(3.0 mL). b Isolated yields. c 1H NMR yields using mesitylene as internal
standard.
Table 2. Evaluation of Acid Additive for the Reaction of
Oxabicyclic Alkene 1a with Terminal Ynone 2aa
a Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), ClCH2CH2Cl
(3.0 mL); isolated yields.
entry
additive (equiv)
CF3CO2H (0.5)
solvent
3a(%)b
tracec
tracec
52
on the reaction revealed that the reaction in CH2Cl2 and
CHCl3 gave slightly lower yields (entries 9 and 10). Using
toluene, THF, or ethyl acetate (EA) as the reaction media
also afforded 3a in low yields (entries 11ꢀ13).
1
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
CH2Cl2
2
2,4,6-F3C6H2CO2H (0.5)
AcOH (0.5)
3
4
PhCO2H (0.5)
46
5
m-NO2C6H4CO2H (0.5)
p-MeOC6H4CO2H (0.5)
ꢀ
52
Under the optimized reaction conditions, the scope of
the substrates of this new type of furan synthesis was
examined, and the results are compiled in Table 3. In
general, treatment of all bicyclic alkenes 1 and terminal
ynones 2 under the effect of palladacycle P3 regiospecifi-
cally furnished the corresponding 2,3,4-trisubstituted fur-
ans 3 in good yields. The reaction tolerated ynones 2 with
various substituents located at the 2-, 3- or 4-positions of
the aryl ring, affording the corresponding furans 3bꢀ3f in
high yield. The use of furanyl substituted ynone led to
a 2,20-bifuran 3h in 78% yield. An ynone with an alkyl
substituent was also tolerated, providing corresponding
furan 3i in 81% yield. It has also been revealed that not
only oxabicyclic alkenes but also norbornene, norborna-
diene, and a furanꢀacetylenedicarboxylate adduct are
suitable substrates to produce substituted furans 3nꢀp. It
was found that the reaction of oxabicyclic alkenes with a
substituent on the aryl ring also proceeded smoothly to
give the substituted furans, though the yields were slightly
lower for 3k, 3l, and 3m. No reactions occurred when
6
76
7
54
8
p-MeOC6H4CO2H (1.0)
p-MeOC6H4CO2H (0.25)
p-MeOC6H4CO2H (0.5)
p-MeOC6H4CO2H (0.5)
p-MeOC6H4CO2H (0.5)
p-MeOC6H4CO2H (0.5)
p-MeOC6H4CO2H (0.5)
74
9
69
10
11
12
13
14
64
CHCl3
67
toluene
46
THF
54
EA
63
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), ClCH2CH2Cl
(3.0 mL). b Isolated yields. c 1H NMR yields using mesitylene as internal
standard.
acids, for example, AcOH and PhCO2H, did not improve
the yield of the reaction compared to that using
p-MeOC6H4CO2H (entries 3ꢀ5 vs entry 6). The impact
of the loading of p-MeOC6H4CO2H was also studied.
Increasing or decreasing the amount of p-MeOC6H4CO2H
exerted a limitedinfluenceon the yield offuran3a(entries 7
and 8 vs entry 6). The investigation of the impact of solvent
5758
Org. Lett., Vol. 14, No. 22, 2012

Scheme 1. Experiments for Identifying the Reaction
Intermediate
Scheme 2. Proposed Reaction Mechanism of Furan Formation
Based on the above experiments and literature,5d we
propose a possible reaction mechanism for furan forma-
tion via the reaction of bicyclic alkene 1 with terminal
ynone 2 (Scheme 2). The terminal ynone 2 reacts with the
monomer of palladacycle P3 to give an alkynylpalladium-
(II) A. Carbopalladation of intermediate A to bicyclic
alkene 1 affords a species B, which undergoes an intra-
molecular addition and a subsequent tautomerization
to furnish an alkylidenecyclopropane C coordinated with
palladacycle P3. Rearrangement of C affords furan 3
accompanying the release of the palladacycle P3.13
In conclusion, we have developed a new synthetic strat-
egy to access polysubstituted furans regiospecifically using
bicyclic alkenes and terminal ynones in an intermolecular
way. The unique catalytic activity of palladacycles has
been demonstrated. A rational mechanism has also been
proposed. This reaction features mild reaction conditions,
easily available starting materials and palladacycle cata-
lysts, a wide substrate scope, and high regiospecificity.
Further studies on the extension of the method as well as
the applications of palladacycles as catalysts in organic
synthesis are underway in our lab.
2,3-dihydrofuran, cyclopentene, and cyclohex-2-enone were
used. So we thought that the bridged ring was important for
this reaction, which could be the result of a release of strain
when the reaction occurred.
To gain a greater understanding of the mechanism of
this unusual furan formation reaction, some experiments
were carried out (Scheme 1). When 4 was treated with
palladacycle P3, no furan product was found (eq 1). Some
clues were provided by monitoring the course of the
1
reaction of oxabicyclic alkene 1a and ynone 2a with H
and 13C NMR spectroscopy (eq 2). When the reaction ran
for 5 min, 1H NMR showed two new peaks at δ 2.00 (d,
J = 7.2 Hz), 2.10 (d, J = 7.6 Hz). These two peaks could
be assigned as two protons on the cyclopropane ring of
the intermediate5 by comparison to that of 7 (δ 1.98 d, J =
7.2 Hz and 2.23 d, J = 7.6 Hz) (eq 3). When the reaction
was allowed to proceed for 40 min, these two peaks
disappeared, and the peaks of protons of furan 3a ap-
peared. 13C NMR gave same information for the forma-
tion of a cyclopropane ring. When the reaction proceeded
for 5 min, two peaks appeared at δ 26.3, 29.4, which have
similar chemical shifts with the two carbons of the cyclo-
propane ring of 7. These two peaks disappeared after
40 min. These NMR experiments offered evidence for
the reaction pathway to furans via alkylidenecyclopropane
5 as the reaction intermediate.8f,13
Acknowledgment. Financial support from the Major
Basic Research Development Program (2011CB808700),
National Natural ScienceFoundation of China(21032007,
21002113, 21121062), Chinese Academy of Sciences, the
Technology Commission of Shanghai Municipality, and
the Croucher Foundation of Hong Kong is greatly
acknowledged.
Supporting Information Available. Experimental proce-
dures, the synthesis of palladacycle P3ꢀP5, and spectro-
scopic data of all newcompounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) (a) Yao, T.; Hong, A.; Sarpong, R. Synthesis 2006, 3605.
(b) Chowdhury, M. A.; Senboku, H.; Tokuda, M. Synlett 2004, 1933.
(c) Nakamura, I.; Yamamoto, Y. Adv. Synth. Catal. 2002, 344, 111.
(d) Siriwardana, A. I.; Nakamura, I.; Yamamoto, Y. J. Org. Chem. 2004,
69, 3202. (e) Siriwardana, A. I.; Kumada, M.; Nakamura, I.; Yamamoto,
Y. J. Org. Chem. 2005, 70, 5932. (f) Dudnik, A. S.; Gevorgyan, V. Angew.
Chem., Int. Ed. 2007, 46, 5195.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 22, 2012
5759