Furan-based o-quinodimethanes by gold-catalyzed dehydrogenative heterocyclization of 2-(1-alkynyl)-2-alken-1-ones: A modular entry to 2,3-furan-fused carbocycles

Article abstract of DOI:10.1002/anie.201403709

A strategy for in situ generation of furan-based ortho-quinodimethanes (o-QDMs) by the gold(I)-mediated dehydrogenative heterocyclization of 2-(1-alkynyl)-2-alken-1-ones in the presence of pyridine N-oxide under mild reaction conditions was developed. These in situ furan-based o-QDMs were trapped by electron-deficient olefins and alkynes, thus furnishing various 2,3-furan-fused carbocycles in good yields with high diastereo- and regioselectivities.

Full text of DOI:10.1002/anie.201403709

Angewandte
Chemie
DOI: 10.1002/anie.201403709
Heterocycle Synthesis
Furan-Based o-Quinodimethanes by Gold-Catalyzed Dehydrogenative
Heterocyclization of 2-(1-Alkynyl)-2-alken-1-ones: A Modular Entry
to 2,3-Furan-Fused Carbocycles**
Liejin Zhou, Mingrui Zhang, Wenbo Li, and Junliang Zhang*
Abstract: A strategy for in situ generation of furan-based
ortho-quinodimethanes (o-QDMs) by the gold(I)-mediated
dehydrogenative heterocyclization of 2-(1-alkynyl)-2-alken-1-
ones in the presence of pyridine N-oxide under mild reaction
conditions was developed. These in situ furan-based o-QDMs
were trapped by electron-deficient olefins and alkynes, thus
furnishing various 2,3-furan-fused carbocycles in good yields
with high diastereo- and regioselectivities.
pyrolysis (FVP > 5508C and 10À4 Torr) of 2-methyl-3-furyl-
methyl ester and 1,4-elimination of 2,3-[2-{(tributylstannyl)-
methyl}furan-3-yl]methylester (Scheme 1a). However, o-
F
uran is a fundamental subunit present in numerous
bioactive natural products, as well as in pharmaceuticals,
molecular electronics, and functional polymers.[1] Moreover,
furan also functions as a versatile building block for the
synthesis of a variety of functional molecules through the
oxidation and cycloaddition reactions.[2] In the past years,
much progress has been made on the synthesis of highly
substituted furans from acyclic precursors,[3,4] However, less
attention has been paid to the synthesis of 2,3-furan-fused
carbocycles,[4] despite the presence of their ubiquitous struc-
tural skeleton in many natural products, such as pinguisone,
furodysinin, and furanoeremophilanes (Figure 1).[5]
Scheme 1. Comparison of previous work and this work. EWG=elec-
tron-withdrawing group.
QDMs generated by the FVP method have not yet been
used in Diels–Alder reactions because of their rapid [4+4]
dimerizations under the reaction conditions.[9] The latter
method is efficient and used in Diels–Alder reactions, but
suffers from the use of toxic tin compounds. With respect to
atom economy and step economy, in situ generation of furan-
based o-QDMs from readily available acyclic precursors
under mild reaction conditions is considered to be the most
straightforward and efficient option.
In contrast, since the elegant work by Larock and co-
workers,[10a] 2-(1-alkynyl)-2-alken-1-ones, which could be
easily prepared on large scale from simple terminal alkynes
and a-bromo-a,b-enones, have emerged as powerful precur-
sors for diversity synthesis.[10,11] In such transition-metal-
catalyzed reactions,[10] metal all-carbon 1,3-dipole intermedi-
ates (Int-A) are commonly proposed, and they react with
a variety of dipolarophiles, thus leading to 3,4-furan-fused
ring systems (Scheme 1b). We envisaged that furan-based o-
QDMs (Int-B) might be generated by the base abstraction of
one proton from the 2-methyl group of Int-A (M = Au). It is
crucial to find an appropriate base that is strong enough to
abstract the proton and is also compatible with the Lewis
acidic metal catalyst. Herein, we report a mild, efficient, and
Figure 1. 2,3-Furan-fused carbocycle in natural products.
A Diels–Alder reaction of furan-based ortho-quinodi-
methanes (o-QDMs)[6,7] with dienophiles is the most straight-
forward approach to 2,3-furan-fused carbocycles. To date,
only a few methods for in situ generation of furan-based o-
QDMs have been reported,[8,9] including flash vacuum
[*] L. Zhou, M. Zhang, Dr. W. Li, Prof. Dr. J. Zhang
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry, East China Normal University
3663 N. Zhongshan Road, Shanghai 200062 (P.R. China)
E-mail: jlzhang@chem.ecnu.edu.cn
Homepage: http://faculty.ecnu.edu.cn/s/1811/t/20975/main.jspy
[**] Financial support from the National Natural Science Foundation of
China (21372084), 973 Programs (2011CB808600), and the
Changjiang Scholars and Innovative Research Team at the Univer-
sity (PCSIRT) is greatly appreciated. We thank Prof. Shengming Ma
for helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403709.
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atom-economic strategy for in situ generation of furan-based
o-QDMs (Int-B) from acyclic 2-(1-alkynyl)-2-alken-1-ones
through a gold-mediated dehydrogenative heterocyclization
aromatic (1g–l), heteroaromatic (1m), and aliphatic (1 f)
groups can be introduced to the products.
In our previous work,[10f] the compound 1n underwent
a domino heterocyclization/1,5-H shift/annulation process to
give the polyheterocycle 4n in 70% yield (Scheme 2). With
in the presence of pyridine N-oxide (involving a challenging
3
À
C(sp ) H activation of the methyl group). A variety of 2,3-
furan-fused carbocycles were obtained in good yields with
high regioselectivity and diastereoselectivity, by reacting Int-
B with a range of electron-deficient olefins and alkynes as
dienophiles (Scheme 1c). To the best of our knowledge, our
work represents the first approach, since Cava reported the
first example of o-QDMs 56 years ago,[6d] toward furan-based
o-QDMs from acyclic precursors.
To test our hypothesis, the compound 1a (see Table 1) and
dienophile tetracyanoethylene (2) were chosen as model
substrates. Because the base is crucial to the realization of this
reaction, a series of inorganic and organic bases, such as
K2CO3, 1,4-diazabicyclo[2,2,2]octane (DABCO), Et3N, and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), were examined
with the use of [Ph3PAuCl] as the catalyst. However, to our
disappointment, no desired product (3a) was observed (for
details, see Table S1 in the Supporting Information). Inspired
by the delicate findings, by the groups of Zhang[12] and Liu,[13]
that N-oxides of 2,6-lutidine, 2,6-dichloropyridine, and nitro-
sobenzene could act as weak bases in some gold-catalyzed
transformations, pyridine N-oxide and nitrosobenzene were
tested. Much to our delight, 89% yield of 3a was isolated
when 0.1 equivalents of pyridine N-oxide was employed as
the weak base.
With the optimized reaction conditions in hand, the
reaction scope was first examined by variation of the 2-(1-
alkynyl)-2-alken-1-ones (Table 1). Halophenyl groups (1c
and 1d) are compatible. To our delight, the [4+2] reactions
of the substrates with R2 = styryl took place regioselectively,
and no product resulting from 6p-electrocyclization of the
furan-based o-QDMs was observed, thus indicating that this
process is highly chemoselective. The substituent effect of R3
on the alkyne moiety was also studied and showed that
Scheme 2. Selective transformations of the compound 1n by two
3
À
different C(sp ) H functionalizations. PMP=para-methoxyphenyl,
Tf =trifluoromethanesulfonyl.
this background, we became curious about whether the
tandem furan-based o-QDM formation and Diels–Alder
reaction could take place, or not, under the present reaction
conditions. To our delight, the reaction worked well to
produce the desired cycloadduct 3n in 82% yield, in which
the morpholine moiety was untouched. Notably, no 4n was
detectable, thus indicating that the pyridine N-oxide can shut
down the competing domino reaction by efficient and rapid
conversion of the 1,3-dipoles into furan-based o-QDMs.
It is interesting to find that a new type of dearomative
cycloadduct (5) was formed, rather than the expected cyclo-
adduct 3o, when the compound 1o, with a butyl group on the
olefinic moiety, was used as the substrate (Scheme 3). The
compound 5 was obtained in 53 and 55% yields, respectively,
under the catalysis of two different gold complexes. Two
plausible reaction pathways (Path A and B) might account for
Table 1: The scope of 2-(1-alkynyl)-2-alken-1-one 1 reacting with 2.
Entry
R2/R3(1)
3
Yield [%][a]
1
2
3
4
5
6
7
8
Ph/Ph (1a)
3a
3b
3c
3d
3e
3 f
3g
3h
3i
89
85
71
74
91
75
77
71
74
73
78
65
85
4-MeOC6H4/4-MeOC6H4 (1b)
4-BrC6H4/Ph (1c)
4-ClC6H4/Ph (1d)
styryl/Ph (1e)
styryl/nBu (1 f)
Ph/4-MeC6H4 (1g)
Ph/4-MeCOC6H4 (1h)
Ph/4-MeO2CC6H4 (1i)
Ph/4-CF3C6H4 (1j)
Ph/4-O2NC6H4 (1k)
Ph/1-naphthyl (1l)
Ph/2-thienyl (1m)
9
10
11
12
13
3j
3k
3l
3m
[a] Yield of the isolated product. DCE=1,2dichloroethane.
Scheme 3. Transformation of 1o and mechanistic study.
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the formation of 5 from the key vinyl furan intermediate Int-
D, which is generated from Int-C by the deprotonation of the
vicinal carbon atom to the carbocation. In Path A, Int-D
could undergo the protonation to give the trisubstituted furan
6, with subsequent Diels–Alder reaction with the dienophile
2. An alternative reaction pathway (Path B) may proceed
through the Diels–Alder reaction first with subsequent
protonation. To gain insight into the reaction mechanism,
some control experiments were carried out. Indeed, the
cycloisomerization reaction of 1o took place in the absence of
2 under the catalysis of AuCl3, thus affording the trisubsti-
tuted furan 6 in 94% yield. In contrast, no reaction occurred
at all with the use of [Ph3PAuCl] as the catalyst, and only 1o
was recovered. The Diels–Alder reaction of furan 6 with 2
worked well in DCE at 608C without the gold catalyst, thus
leading to 5 in 72% yield. All these results strongly support
the proposal that the reaction might proceed through Path A
under the catalysis of AuCl3, and Path B under the catalysis of
[Ph3PAuCl].
spirocyclic oxindole scaffolds 10a and 10b[14] were also
efficiently constructed (97–98% yields) with moderate dia-
stereoselectivity. To our delight, the naphtho[2,3-b]furan-5,8-
dione skeleton 13,[14] a key subunit in a number of natural
products with biological activities, was obtained in 57% yield
with the use of benzoquinone as both dienophile and oxidant.
We then turned our attention to the electron-deficient
alkynes such as acetylenedicarboxylates as the dienophiles
(Table 3). Halophenyl groups (14b and 14c) could be
Table 3: The reaction of 2-(1-alkynyl)-2-alken-1-ones 1 with DMAD.
Entry
R2/R3/R (14)
t [h]
Yield [%][a]
1
2
3
4
5
6
7
8
Ph/Ph/Me (14a)
12
8
8
6
6
12
12
6
70
70
75
64
79
50
52
52
77
62
59
76
4-ClC6H4/Ph/Me (14b)
4-BrC6H4/Ph/Me (14c)
Ph/4-MeC6H4/Me (14d)
Ph/4-MeOC6H4/Me (14e)
Ph/4-CF3C6H4/Me (14 f)
Ph/4-NO2C6H4/Me (14g)
Ph/1-naphthyl/Me (14h)
Ph/2-thienyl/Me (14i)
Ph/1-cyclohexenyl/Me (14j)
Ph/n-C4H9/Me (14k)
Ph/Ph/Et (14l)
Similarly, the cyclic precursor 1p [Eq. (1)] could undergo
the domino cycloisomerization and Diels–Alder reaction with
9
8
10
11
12
10
10
12
[a] Yield of the isolated product.
2 under the catalysis of AuCl3 in DCE at 608C, thus furnishing
60% yield of the tricyclic compound 7,[14] which has an
important and synthetically challenging bridged skeleton. The
maleic anhydride was also applicable to this reaction, thus
furnishing the tetracycle 8 in 63% yield. The anhydride
moiety of 8 is a useful functional group for synthesis of
a variety of compounds.
To our delight, various electron-deficient olefins such as 2-
arylidene-malononitrile, maleic anhydride, N-aryl maleimide,
and benzoquinone could be used as dienophiles (Table 2),
thus furnishing the corresponding products 9–13 in good
yields under the catalysis of [Ph3PAuCl]/AgO2CC3F7 (for
more results using other silver salts, see Table S2). For
example, the reaction of 1a with N-phenyl maleimide
afforded 84% yield of the furan-fused tricycle 12a.[14] The
introduced to the products. Variation of the electronic
nature of the phenyl ring on the alkyne moiety (R3) showed
that electron-rich substrate gave higher yields than those with
electron-deficient ones (Table 3, entry 5 versus entries 6 and
7). In addition to the substituted phenyl groups, 1-naphthyl
and 2-thienyl were compatible with this reaction, thus
furnishing the products 14h and 14i in 52 and 77% yield,
respectively (Table 3, entries 8 and 9). Moreover, it should be
noted that 1-cyclohexenyl- and n-C4H9-substituted yne-
enones afforded the desired products in moderate yields
(Table 3, entries 10 and 11). The diethyl acetylene dicarbox-
ylate produced the corresponding product 14l in 76% yield.
Moreover, benzofuran could be easily obtained by oxidation
of 14 [see Equation (S1) in the Supporting Information].
In summary, we have developed an unprecedented
strategy for access to furan-based o-QDMs by gold-catalyzed
dehydrogenative annulation of 2-(1-alkynyl)-2-alken-1-ones
in the presence of pyridine N-oxide under mild reaction
conditions. These reactive 1,3-dienes can be trapped by
various dienophiles, including electron-deficient olefins and
alkynes, and thus provides facile access to highly substituted
furan-fused carbocycles with high diastereo- and regioselec-
tivities. Furthermore, when aliphatic-substituted 2-(1-
alkynyl)-2-alken-1-ones were used, a novel dearomative
Diels–Alder reaction was observed, thus efficiently furnishing
2,3-dihydrofuran-fused carbocycles. The salient features of
this strategy include mild reaction conditions, readily avail-
able starting materials, atom-economy, and general substrate
Table 2: Other electron-deficient olefins as dienophiles.
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and synthetic applications of this transformation is underway
and will be reported in due course.
Received: March 25, 2014
Published online: && &&, &&&&
Keywords: cycloaddition · gold · heterocycles · nitrogen oxides ·
.
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Heterocycle Synthesis
L. Zhou, M. Zhang, W. Li,
J. Zhang*
&&&& — &&&&
Furan-Based o-Quinodimethanes by
Gold-Catalyzed Dehydrogenative
Heterocyclization of 2-(1-Alkynyl)-2-alken-
1-ones: A Modular Entry to 2,3-Furan-
Fused Carbocycles
Caught in a trap: A novel strategy for in
situ generation of furan-based ortho-qui-
nodimethanes (o-QDMs) using the title
reaction was developed. These furan-
based o-QDMs were trapped by electron-
deficient olefins and alkynes, thus leading
to various 2,3-furan-fused carbocycles in
good yields with high diastereo- and
regioselectivities. EWG=electron-with-
drawing group.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!