Zinc-catalyzed [4+3] cycloaddition with concomitant furan annulation: Formation of cyclohepta[b]furans

Article abstract of DOI:10.1002/chem.201402513

A convenient zinc-promoted [4+3] cycloaddition of a carbonyl ene-yne with simple dienes was first achieved. This reaction provided an efficient strategy to prepare various cyclohepta[b]furan rings by cascade cycloadditions. Additionally, a multicomponent reaction of dione, alkynal, and diene was also reported, which exhibited a novel strategy for selective creations of C-O bonds and C-C bonds. Go tandem! A first zinc-catalyzed tandem [4+3] cycloaddition is presented herein. Various substituted cyclohepta[b]furans were synthesized from carbonyl ene-yne and diene in moderate to good yield. Furan rings and seven-membered rings were prepared in one single step (see scheme; TBS=tert-butyldimethyl).

Full text of DOI:10.1002/chem.201402513

DOI: 10.1002/chem.201402513
Communication
&
Organic Synthesis
Zinc-Catalyzed [4+3] Cycloaddition with Concomitant Furan
Annulation: Formation of Cyclohepta[b]Furans
Bo Song, Lian-Hua Li, Xian-Rong Song, Yi-Feng Qiu, Mei-Jin Zhong, Ping-Xin Zhou, and
Yong-Min Liang*[a]
Abstract: A convenient zinc-promoted [4+3] cycloaddi-
tion of a carbonyl ene–yne with simple dienes was first
achieved. This reaction provided an efficient strategy to
prepare various cyclohepta[b]furan rings by cascade cyclo-
additions. Additionally, a multicomponent reaction of
dione, alkynal, and diene was also reported, which exhibit-
ed a novel strategy for selective creations of CÀO bonds
Scheme 1. Cycloaddition of dienes with furfuryl alcohols.
and CÀC bonds.
ring.[5] Among the numerous strategies, the [4+3] cycloaddi-
tion[6] (Scheme 1a) was regarded to be an effective and
Seven-membered-ring-fused furans are important building
blocks that are widely found in lots of natural products
(Figure 1). Such compounds have been identified to have sig-
straightforward one. In 2011, Johan M. Winne and co-workers
first reported an elegant [4+3] cycloaddition between diene
and furfuryl cations to achieve cyclohepta[b]furans, by using
furfuryl alcohols as precursors of allylic cations (Scheme 1b).[7]
This work was innovative from a synthetic point of view, but
a new synthetic strategy for the synthesis of multicyclic skele-
tons with high convenience warrants further investigation.
Due to the convenience and efficiency in organic synthesis,
tandem cyclizations have been studied with great depth in
recent years. In 2013, a tandem cyclization to achieve cyclo-
hepta[b]indoles was disclosed by Tang and his colleagues.[8] In
this report, the seven-membered-ring-fused indole was synthe-
sized involving a synchronous formation of indole. However,
the construction of both a furan ring and a seven-membered
ring in one step has not yet been reported. Our group has also
reported several Lewis acid catalyzed tandem cyclizations.[9]
From our point of view, cascade reactions to achieve the cyclo-
hepta[b]furans are highly desirable.
Figure 1. Representative cyclohepta[b]furans.
nificant therapeutic values: frondosin B is used as an interleu-
kin-8 receptor antagonist,[1] liphagal has inhibitory activity
against PI3K with an IC50 of 100 nm,[2] and myrrhterpenoid H
has been reported to have neuroprotective effects.[3] Due to
the excellent biological and pharmic activities of these com-
pounds, the construction of the cyclohepta[b]furan ring sys-
tems has become a topic of great interest among synthetic
chemists.[4] The key step to achieving the seven-membered-
ring-fused furan is the formation of the seven-membered
Previously, Vicente and Lꢀpez with their colleagues present-
ed a catalytic generation of zinc furylcarbenes derived from
carbonyl ene–yne compounds (Scheme 2).[10] On the basis of
their work and our strategies toward tandem cyclization,
herein we first report a convenient cascade reaction to con-
struct seven-membered-ring-fused furans. Two possible routes
were proposed to realize this tandem cyclization: the carbonyl
furylcarbene intermediate reacts with one single side of the
diene, creating a cyclopropane product followed by a [3,3]sig-
matropic/Cope rearrangement to generate the seven-mem-
bered ring (Scheme 2, path a), or the furylcarbene forms a car-
bocation by tautomerization and then undergoes a [4+3] cy-
cloaddition with diene to form the anticipated cyclohepta[b]-
furan ring (Scheme 2, path b).
[a] B. Song, L.-H. Li, X.-R. Song, Y.-F. Qiu, M.-J. Zhong, P.-X. Zhou,
Prof. Dr. Y.-M. Liang
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou 730000 (P.R. China)
E-mail: liangym@lzu.edu.cn
We began our study by examining 1a and 2a as the model
substrates in the presence of ZnCl2 as the catalyst (Table 1).
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402513.
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transition-metal catalysts were
also tested and only platinum
salts resulted in the aimed prod-
uct in poor yields (entries 13–
16). From the above results, the
reaction conditions were af-
firmed: 1.0 equivalent of 1a,
5.0 equivalents of 2a, 20 mol%
of ZnCl2 in toluene at 1008C for
0.5 h.
With the optimal conditions in
hand, the scope of this reaction
with respect to substrates 1 and
2 was studied (Table 2). Gratify-
ingly, a series of cyclohepta[b]-
furans (3aa, 3ac–3as, 3au–3bl)
were gained in moderate to
good yields. The structure of
product 3ak was confirmed by
X-ray crystal structural analysis.[11]
Obviously, steric effects signifi-
Scheme 2. Lꢀpez’s work and our anticipation towards this work.
Table 1. Reactions of 1a with 2a under different conditions.[a]
cantly affect the reaction: ortho-
substituted material 2b lead to
only trace amount of the product (Table 2, entry 2), whereas
meta- and para- substituted substrates resulted in good yields
of the corresponding products (entries 3 and 4). Meanwhile,
electronic effects also influenced the reaction to some extent.
Substrates with electron-donating groups (EDG) gave the de-
sired products in moderate to good yields (entries 2–9). Elec-
tron-withdrawing groups (EWG) on the aromatic rings could
also lead to the corresponding products in lower yields than
that of EDG (entries 10–14). It was found that the nitro group
as well as the halogen atoms were all tolerated (entries 14–19).
To our disappointment, only trace amounts of the product
were detected when replacing the phenyl group with an alkyl
group (entry 20). Interestingly, when aromatic rings were put
beside the carbonyl groups, the desired products were isolated
in good yields (entries 21 and 22). We believed that a carbocat-
ion stabilization group was indispensable, and an EDG on the
phenyl ring was more effective in stabilizing the carbocation
(Scheme 4).
Entry
Solvent
Catalyst
T [8C]
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
dichloromethane
anisole
1,4-dioxane
MeNO2
1,2-dichloroethane
toluene
toluene
toluene
toluene
toluene
toluene
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
80
80
80
80
80
1
1
1
trace
trace
25
51
55
68
65
80
75
70
50
trace
28
35
0.8
0.6
0.7
0.5
0.5
0.5
0.5
0.5
1
0.5
0.6
0.8
2
80
120
100
100
100
100
100
100
100
100
100
9
ZnBr2
ZnI2
10
11
12
13
14
15
16
Zn(OTf)2
Zn(OAc)2
PtCl2
Pt(PPh3)2Cl2
Cu(OTf)2
Sc(OTf)3
toluene
toluene
toluene
toluene
In addition, monosubstituted diene 1b could also lead to
the corresponding product in moderate yields (Table 2, en-
tries 23 and 24). Meanwhile, ketone product 3ba was success-
fully isolated (entry 23). When furan was used as the diene
(entry 25), only trace amount of the corresponding product
was observed.
trace
trace
toluene
[a] Reaction conditions: 0.2 mmol of 1a, 5.0 equiv of 2a, 20 mol% metal
catalyst, 1.0 mL solvent, Ar atmosphere, unless otherwise noted. [b] Isolat-
ed yield.
Several solvents could lead to the target product at
808C, among which toluene gave the relative better
yield (Table 1, entries 3–6). The best yield of 80% was
obtained in toluene by setting the temperature at
1008C (entry 8). Further studies on catalysts indicated
that several other zinc salts, such as ZnBr2, ZnI2, and
Zn(OTf)2 could be used as alternative catalysts de-
spite the unsatisfactory yields (entries 9–11). Other Scheme 3. Verification experiment.
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Communication
to form the target seven-membered ring.[12] When 1a and 2a
were used as the substrates, the cyclopropane product 4 could
be isolated at 508C (Scheme 3).[13] When compound 4 was
stirred at 1008C in the presence of ZnCl2, our expected prod-
uct 3aa was not detected all the time. This indicated that the
[3,3]sigmatropic/Cope rearrangement might not be included in
this transformation, the reaction might go through a carbocat-
ion path.
Table 2. Zinc-catalyzed reactions of carbonyl ene–yne derivatives with di-
enes.[a]
A plausible mechanism that is consistent with the experi-
mental results and literature precedent[14] is shown in
Scheme 4. Single-crystal structure and 1H NMR spectroscopic
analysis confirmed the structure of the corresponding products
to be form A (Scheme 2). In fact, activated by the zinc cation,
the CꢀC bond was attacked by the carbonyl group to give
a furan ring, forming a zinc carbine at the benzyl position.[15]
Zinc carbine would tautamerize into an allylic cation and then
went through a [4+3] cycloaddition with diene 1a to form
a seven-membered ring. Finally, the zinc metal detached from
the skeleton, donating the electron to the neighboring bond
to form a carbon–carbon double bond, and the final product
3aa was achieved.
Next, considering that zinc chloride can catalyze some Knoe-
venagel reactions,[16] a multicomponent reaction was devel-
oped using 5, 6, and 1a as the substrates, synthesizing 3aa in
a direct way (Scheme 5). We were glad to find that a mixture
of dione 5 (1.0 equiv), alkynal 6 (1.0 equiv), and diene 2a
(5.0 equiv) with 20 mol% of ZnCl2 at 1108C for 2.5 h afforded
the desired product. Despite the low yield, this one-pot reac-
tion opened up a new route to build ring systems, providing
a convenient route for the selective construction of C–C and
C–O bonds.
Entry
1
2
Product
Yield [%][b]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
2a (R2 =Ph)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
80
trace
71
78
68
66
60
63
55
57
50
50
48
30
50
52
65
2b (R2 =o-MePh)
2c (R2 =m-MePh)
2d (R2 =p-MePh)
2e (R2 =p-EtPh)
2 f (R2 =p-nPrPh)
2g (R2 =p-tBuPh)
2h (R2 =p-OMePh)
2i (R2 =m-OMePh)
2j (R2 =p-COOCH3Ph)
2k (R2 =p-COCH3Ph)
2l (R2 =m-COCH3Ph)
2m (R2 =p-CF3Ph)
2n (R2 =p-NO2Ph)
2o (R2 =p-FPh)
9
10
11
12
13
14
15
16
17
18
19
20
3aj
3ak
3al
3am
3an
3ao
3ap
3aq
3ar
3as
3at
2p (R2 =m-FPh)
2q (R2 =p-ClPh)
2r (R2 =m-ClPh)
2s (R2 =p-BrPh)
2t (R2 =n-Pr)
59
68
trace
21[c]
1a
1a
1b
70
80
58
In conclusion, we have disclosed a novel [4+3] cycloaddition
to synthesize seven-membered skeletons. This process enables
an efficient synthesis strategy of different cyclohepta[b]furan
rings, using cheap and nontoxic zinc chloride as the catalyst.
Both the furan rings as well as the seven-membered rings
were constructed in one single step. More applications of this
kind of reaction are still on the way.
22
Experimental Section
23[d]
2a
Typical procedure for the preparation of compound 3aa
Compound (1a) (198.0mg, 1.0mmol, 5.0 equiv) and toluene
(1.0mL) was added under Ar to a flask containing 2a (42.4mg,
0.2mmol, 1.0 equiv) and zinc chloride (5.4mg, 0.04mmol,
0.2 equiv). The mixture was stirred at 1008C for 0.5h and the re-
sulting mixture was extracted with ethyl ethanoate, washed with
brine, dried over Na2SO4, evaporated under vacuum, and purified
by flash column chromatography (hexane/triethylamine=100:1)
24
25
1b
1c
2q
2a
3bq
3ca
55
trace
[a] Reaction conditions: 0.2 mmol of 1a, 5.0 equiv of 2a, 20 mol% ZnCl2,
1.0 mL solvent, Ar atmosphere, unless otherwise noted. [b] Isolated yield.
[c] Double-bond geometry of compound 2u was proven by 1H NMR spec-
troscopy and NOE studies. [d] The product was treated with 4m HCl.
Acknowledgements
To investigate the mechanism for this zinc-catalyzed cycload-
dition, further experiments were carried out. As depicted in
Scheme 2, furylcarbene could react with one single side of the
diene to form a cyclopropane product,[10] such a 1,5-diene was
reported to undergo a [3,3]sigmatropic/Cope rearrangement
We thank the National Science Foundation (NSF, 21072080),
National Basic Research Program of China (973 Program,
2010CB833203), the Program for Changjiang Scholars and In-
novative Research Team in University (IRT1138), and the Funda-
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Keywords: cycloadditions
· carbocations · heterocycles ·
tandem cyclization · zinc catalysis
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Received: March 7, 2014
Published online on April 11, 2014
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