From cyclopropenes to tetrasubstituted furans: Tandem isomerization/ alkenylation sequence with Cu/Pd relay catalysis

Article abstract of DOI:10.1002/chem.201203997

Pon de relay: A convenient and efficient synthesis of alkene-functionalized furans from cyclopropenes, which proceeds through an isomerization/olefination cascade sequence under copper-palladium relay catalysis, has been developed (see scheme). Copyright

Full text of DOI:10.1002/chem.201203997

DOI: 10.1002/chem.201203997
From Cyclopropenes to Tetrasubstituted Furans: Tandem Isomerization/
Alkenylation Sequence with Cu/Pd Relay Catalysis
Chuanling Song, Lin Ju, Mingchao Wang, Pengcheng Liu, Yuanzhe Zhang,
Jianwu Wang,* and Zhenghu Xu*[a]
Furans represent an impor-
tant class of five-membered
heterocycles that are prevalent
in a number of biologically
active natural products and
pharmaceuticals.[1] They are
also useful building blocks in
organic synthesis.[2] Thus, many
synthetic methods[3] have been
developed for the synthesis of
furan rings, such as the con-
Scheme 1. Intermolecular dehydrogenative Heck reaction of cyclopropene 1a with alkene 2a.
densation of 1,4-dicarbonyl
compounds (Paal–Knorr syn-
thesis)[4] and the Feist–Benary
synthesis.[5] However, these methods suffer from their inabil-
ity to provide furans that contain sensitive functional groups
with high flexibility. Therefore, new and efficient methods
for the synthesis of polysubstituted functionalized furan de-
rivatives from simple and readily available starting materials
under mild reaction conditions are of significant value.
struction of alkene-functionalized tetrasubstituted furans[8]
with high diversity (Scheme 1).
The intermolecular dehydrogenative Heck reaction[9] has
emerged as an attractive and powerful method for the cou-
À
À
pling of Ar H groups and alkenes. In this process, a C C
À
bond is formed from two C H bonds, thereby eliminating
The current furan syntheses can be generally divided into
two categories: The first involves the construction of the
heterocyclic core by the cyclization of acyclic substrates. For
example, several groups have developed efficient syntheses
of furan compounds by the metal Lewis acid promoted cy-
cloisomerization of alkynyl, allenyl, and cyclopropenyl sub-
strates.[6] However, this method requires the synthesis of
complicated starting materials and is limited by its unpre-
dictable regioselectivity. The second category involves the
introduction of functional groups onto an existing furan
ring.[7] Herein, we report a new method that combines these
two categories in a one-pot cycloisomerization/functionaliza-
tion cascade by employing an intermolecular dehydrogena-
tive Heck reaction (DHR) between a cyclopropene and an
alkene. This intermolecular approach allows for the con-
the arene-activation step in the classic Heck reaction. This
reaction has received great interest over the past few years.
Different transition metals, including Pd,[10] Ru,[11] and
Rh,[12] can catalyze this process. Previous research has fo-
cused on the incorporation of new directing groups, coupling
with unactivated alkenes, tuning regioselectivity by elaborat-
ing different ligands, and so on. The general mechanism in
all of these processes is initiated by the directed or non-di-
À
rected insertion of the metal into the C H bond, thereby
generating a carbon–metal species, followed by the normal
Heck process, and finally the regeneration of the metal cata-
lyst by the oxidant. Because the first electrophilic metal in-
À
sertion into the C H bond requires high activation energy,
these reactions usually require harsh conditions, such as
high temperature, a strong acid additive, and prolonged re-
action time. We proposed that, if we can avoid this direct
À
C H metalation step but use another method to form the
key carbon–metal species, the reaction efficiency can be
greatly improved.
Cyclopropene shows unique and interesting reactivities in
the presence of a transition metal because of its tremendous
ring strain.[13] In our attempts to generate 1,1,2,3-tetrasubsti-
tuted cyclopropenes through DHRs between cyclopropene
[a] C. Song, L. Ju, M. Wang, P. Liu, Y. Zhang, Prof. J. Wang, Prof. Z. Xu
Key Lab for Colloid and Interface Chemistry of
Education Ministry
School of Chemistry and Chemical Engineering
Shandong University, Jinan 250100 (P.R. China)
E-mail: jwwang@sdu.edu.cn
xuzh@sdu.edu.cn
À
1a and an alkene, based on an ester-group-directed C H ac-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203997.
tivation process,[14] to our surprise, we did not isolate any
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COMMUNICATION
1,1,2,3-tetrasubstituted cyclopropene (P) under our opti-
mized reaction conditions. Instead, tetrasubstituted furan 3a
was obtained, as confirmed by X-ray diffraction and NMR
spectroscopy (Scheme 1). A mechanistic study indicated an-
other Cu/Pd relay catalytic sequence that was different from
terion played an important role in the reaction (Table 1, en-
tries 4–6). To our delight, when three equivalents of DMSO
were added to MeCN as the additive, the efficiency of this
reaction was greatly improved.[16] The reaction was complete
within 1 h in 76% yield (Table 1, entry 7).[17] Increasing or
decreasing the amount of DMSO did not lead to better re-
sults (Table 1, entries 8 and 9). Under some conditions, a
small amount of trisubstituted furan 4a was isolated as the
by-product. Using other palladium catalysts (Table 1, en-
tries 10–12) or changing the temperature to 408C and 808C
(Table 1, entries 13 and 14) produced less-satisfactory re-
sults. Finally, the efficiency of the reaction was tested by
using 1 mol% of the catalyst, which gave the product in
48% yield, along with the isomerized furan 4a in 30%
yield, after 30 min (Table 1, entry 15).
À
the general C H metalation process. Herein, we report our
preliminary results.
Initially, we explored the viability of this DHR process in
the reaction of cyclopropene 1a with methyl acrylate (2a).
Gratifyingly, the use of Pd
ACHTUNGRTEN(NUNG OAc)2 (5 mol%) as the catalyst
and Cu(OAc)2 (2 equiv) as the oxidant at 608C in MeCN af-
ACHTUNGTRENNUNG
forded a major product in 21% yield. NMR and MS data
were in accord with the formation of the DHR product (P),
except that the resonance of the two methyl ester groups
from the cyclopropene was shifted. This puzzling question
was not finally resolved until we obtained the X-ray crystal
structure of the product. Indeed, the product was not cyclo-
propene P, but instead isomerized tetrasubstituted furan 3a
(Scheme 1).[15]
Inspired by this result, we continued to optimize the reac-
tion conditions to develop an efficient catalytic system for
the synthesis of the all-substituted furan. We began our ex-
ploration by screening different oxidants and we found that
Control experiments confirmed that both the copper and
palladium catalysts were necessary in this process. Only the
isomerized product (4a) was formed without the palladium
catalyst (Table 1, entry 16) and no product was formed with-
out the copper catalyst (Table 1, entry 17).
With the optimal conditions in hand, that is, the use of
PdACHTNUGTRENNUG(OAc)2 (5 mol%), CuHCATUNGTREN(NUGN OAc)2 (2 equiv), and DMSO
(3 equiv) at 608C in MeCN, we examined the scope of this
transformation. A series of cyclopropenes were reacted with
methyl acrylate and the results are summarized in Table 2.
Both aromatic cyclopropenes and aliphatic cyclopropenes
can all generate their corresponding products in moderate-
to-good yields. An unsubstituted cyclopropene dicarboxylate
substrate also provided 2,3,5-trisubstituted furan 3d in 58%
yield. Halogen atoms, such as Br and F, and a
phenol group were tolerated in this reaction. The
reaction of a cyclopropene that was derived from
ethyl acetoacetate was more difficult in this trans-
formation. Slow injection of the cyclopropene and
increasing the palladium catalyst loading to
10 mol% afforded the 2-alkyl-tetrasubstituted furan
(3k) in 53% yield. In addition, this reaction can be
only Cu
entries 1–6). The use of other oxidants (tert-butyl hydroper-
oxide, benzoquinone, PhI(OAc)2, air; see the Supporting In-
formation for details) resulted in no coupled product. Other
copper salts, including CuCl2, CuSO4, and Cu(ClO4)2, were
ACHTUNGTRENNUNG(OAc)2 and AgOAc gave promising results (Table 1,
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
also ineffective as oxidants, which indicated that the coun-
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(tfa)2
[Pd(PPh3)4]
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Oxidant
Cu(OAc)2
BQ
AgOAc
CuCl2
Additive (equiv)
Yield [%][b]
scaled up to the gram scale without showing a de-
crease in reaction efficiency and yield (see the Sup-
porting Information).
1
2
3
4
5
6
7
8
9
10
11
12
13[d]
14[e]
15[f]
16[g]
17[h]
G
E
–
–
–
–
–
21
0
34
ACHTUNGTRENNUNG
R
Next, the scope of the alkene was explored
(Table 3). A variety of electron-deficient alkenes,
including different acrylates and N,N-dimethyl
acrylamide, proceeded smoothly and efficiently to
produce the corresponding products in generally
good yields. More importantly, the reaction was suc-
cessful for disubstituted alkenes, such as methyl
crotonate (product 3p) and methyl methacrylate
(products 3q and 3q’). These results are remarka-
ble, owing to the low reactivity of disubstituted al-
kenes.[18] In this case, the reaction does not require
the addition of any ligand or much excess of the
alkene and the coupled product can be formed in
moderate yield within 2 h. With methyl methacry-
late, only trace amounts of 3q’ was formed, accord-
E
trace
trace
trace
76
65 (17)
31
60
76
42
32
R
CuSO4
R
Cu
A
–
N
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
N
DMSO (3)
DMSO (1)
DMSO[c]
DMSO (3)
DMSO (3)
DMSO (3)
DMSO (3)
DMSO (3)
DMSO (3)
DMSO (3)
DMSO (3)
N
R
R
R
E
T
58
A
48 (30)
0 (68)
0
–
PdN
–
[a] Reaction conditions: cyclopropene 1a (0.2 mmol), methyl acrylate (2a, 0.4 mmol),
Pd catalyst (5 mol%), oxidant (0.4 mmol), MeCN (1 mL), 608C. [b] Yield of isolated
product; the number in parentheses represents the yield of by-product 4a. [c] DMSO
was used as the solvent. [d] 408C. [e] 808C. [f] Catalyst (1 mol%), 30 min. [g] Only
1
ing to H NMR spectroscopy and TLC analysis (3q/
CuACHTUNGTRENNUNG(OAc)2. [h] Only PdACHTUNGTRENNUNG(OAc)2 (5 mol%) or [PdCl2ACHTNUGTRENN(UGN MeCN)2] (5 mol%). BQ=1,4-ben-
zoquinone, TFA=trifluoroacetate.
3q’, 10:1), and the major isomer (3q) was formed
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3585

J. Wang, Z. Xu et al.
Table 2. Substrate scope of the cyclopropene.[a]
propene, we performed the reaction with one equivalent of
PdACTHNUTRGEN(UGN OAc)2 without any other oxidant. We found that no
Heck product (P) or furan product were produced
(Scheme 2, Equation (1)). This result clearly indicated that
À
Pd
under these condition and ruled out path A.
It has been reported that CuI and Cu
N
(acac)2 (acac=ace-
ACHUTNGRENtNUG ylACHUTNGTRENaNNGU cetonate) can catalyze the isomerization of cyclopropene
into trisubstituted furan,[14] and we also isolated furan 4a as
the by-product. Recently, several groups have reported the
DHRs of furans with different alkenes by using PdACHTUNGTRENNUNG(OAc)2
as an efficient catalyst.[19] These data indicate that the reac-
tion might proceed along path B. However, we noticed that
the DHR of a furan requires either quite harsh reaction
conditions (high temperature, acid additive) or a prolonged
reaction time. Thus, furan 4a and methyl acrylate (2a) were
subjected to the standard reaction conditions and, to our
great surprise, this reaction was very slow and furan 4a was
not consumed, even after 24 h; the final product (3a) was
obtained in only 28% yield after 24 h. Such a striking con-
trast in the reaction rate shows that path B is not likely.
Therefore, we performed kinetic experiments to probe
the reaction mechanism (for details, see the Supporting In-
formation). The standard reaction of compound 1a with
compound 2a was monitored by crude 1H NMR analysis
after work-up at an indicated time (Figure 1). Cylopropene
1a was consumed very fast and some compound 4a was gen-
erated, but it has completely disappeared after 1 h.
[a] Reaction conditions: cyclopropene 1 (0.2 mmol), methyl acrylate (2a,
0.4 mmol), Pd
ACHTUNGTRENNUNG(OAc)2 (5 mol%), CuACTHUNGTRENNNUG
DMSO (0.6 mmol), 608C. [b] With Pd
AHCTUNGTRENNUNG
According to these data, we proposed a copper/palladium
relay mechanism (Scheme 3). It is generally accepted that
copper acetate reacts with cyclopropene, thereby
tion of the cyclopropene over 1 h.
generating the copper carbene intermediate C, fol-
lowed by intramolecular cyclization leading to the
Table 3. Substrate scope of the electron-deficient alkene.[a]
carbonyl ylide species D, which undergoes a deme-
talation process to afford the furan intermediate 4,
as reported.[14] On the other hand, if the ylide D
lost HOAc via the six-membered ring transition
state TS1, a furan copper intermediate (E) would
be produced. Subsequent transmetalation to gen-
erate the key furan–palladium intermediate F
(possibly stabilized by DMSO), followed by regu-
lar insertion into the alkene and b-H elimination,
would afford the products. Finally, the Pd0 is oxi-
dized by CuACTHUNRGTNEUNG(OAc)2 to regenerate the catalyst.
Although we can not currently directly confirm
this Cu/Pd relay sequence, this mechanism can ex-
plain all of the reaction details: 1) Because two
equivalents of CuACHTUNTRGNEUNG(OAc)2 are used, the isomeriza-
[a] Reaction conditions: cyclopropene 1 (0.2 mmol), methyl acrylate (2a, 0.4 mmol),
Pd
(OAc)2 (5 mol%), Cu
E
tion step into the furan–copper complex will be
very fast, which is in accord with the fast con-
sumption of the cyclopropene; 2) this reaction
EWG=electron-withdrawing group.
À
pathway avoids a C H metalation step, which nor-
in 46% yield, probably because of faster b-H elimination,
owing to lower steric hindrance.[18c]
Two possible reaction pathways can be rationalized for
this transformation (path A and B, Scheme 2). To examine
mally requires high energy input, and thus the reaction pro-
ceeds at a very fast rate; 3) the unreacted furan–copper spe-
cies E will generate furan intermediate 4 during work-up,
which is in accord with the parabola shape of this intermedi-
ate; 4) the six-membered ring transition state TS1 is very
À
the possible palladium-catalyzed Csp2 H activation of cyclo-
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Chem. Eur. J. 2013, 19, 3584 – 3589

From Cyclopropenes to Tetrasubstituted Furans
COMMUNICATION
important for the formation of
furan–copper species
E be-
cause other copper compounds,
such as CuCl2 and CuSO4, do
not work as well as CuACHTUNGTRENNUNG(OAc)2.
In summary, we have devel-
oped a convenient and effi-
cient synthesis of tetrasubsti-
tuted
alkene-functionalized
furans from cyclopropenes. An
isomerization/olefination cas-
cade sequence was achieved by
using copper/palladium relay
catalysis. The most important
feature of this procedure is the
transmetalation relay strategy,
which is significantly different
Scheme 2. Possible reaction pathway and control experiments.
À
from the general C H activa-
tion mode. More importantly,
the reaction efficiency is greatly
improved by using equivalent
amounts of a cheap metal cata-
lyst and catalytic amounts of a
precious metal catalyst. These
results will provide an alterna-
tive insight into reaction design
and organic synthesis. Further
mechanism investigation and
other synthetic applications of
this strategy are currently un-
derway in our laboratory.
Experimental Section
A
mixture of Pd
ACHTUNGTRENNUNG
0.01 mmol, 5 mmol%) and CuACHTUNGTRENNUNG
(79.6 mg, 0.4 mmol, 2 equiv) was dis-
solved in MeCN (1 mL) and DMSO
(45.6 mg, 0.6 mmol, 3 equiv), then
compound 1a (42.4 mg, 0.2 mmol) and
compound 2a (34.4 mg, 0.4 mmol,
2 equiv) were added. The resulting
mixture was stirred at 608C until the
reaction was complete (by TLC analy-
sis). The reaction mixture was filtered
and evaporated under reduced pres-
sure and purified by column chroma-
tography on silica gel to give the pure
product (3a).
Figure 1. Kinetic study of the cross DHR reaction.
CCDC 905895 (3a) contains the sup-
plementary crystallographic data for
this paper. These data can be obtained
free of charge from The Cambridge
Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Scheme 3. Proposed relay mechanism for the copper/palladium catalysis.
Chem. Eur. J. 2013, 19, 3584 – 3589
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J. Wang, Z. Xu et al.
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Acknowledgements
We are grateful for financial support from the Natural Science Founda-
tion of China (21102085), the Science Foundation of the Ministry of Edu-
cation of China (20110131120049), the Natural Science Foundation of
Shandong Province (BS2012YY006), and Shandong University. We thank
Prof. Dr. Daofeng Sun and Dr. Di Sun for the analysis of the X-ray struc-
ture.
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Keywords: copper
·
cyclopropenes
·
heterocycles
·
isomerization · transmetalation
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Chem. Eur. J. 2013, 19, 3584 – 3589

From Cyclopropenes to Tetrasubstituted Furans
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Received: November 8, 2012
Revised: December 30, 2012
Published online: February 21, 2013
Chem. Eur. J. 2013, 19, 3584 – 3589
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3589