Palladium-catalyzed carbene/alkyne metathesis with enynones as carbene precursors: Synthesis of fused polyheterocycles

Article abstract of DOI:10.1039/c7cc08221e

An unprecedented palladium-catalyzed novel carbene/alkyne metathesis cascade reaction of alkyne-tethered enynones is described. This reaction affords fused polyheterocycles in moderate to good yields. The transformation begins with Pd-catalyzed 5-exo-dig cyclization of the enynone to form the donor/donor metal carbene, which then undergoes metathesis with the alkyne followed by electrophilic aromatic substitution.

Full text of DOI:10.1039/c7cc08221e

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Palladium-catalyzed carbene/alkyne metathesis with enynone as
carbene precursor: synthesis of fused polyheterocycles
Yang Zheng,a Ming Bao,a Ruwei Yao,a Lihua Qiu*a and Xinfang Xu*ab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An unprecedented palladium-catalyzed novel carbene/alkyne
metathesis cascade reaction of alkyne-tethered enynones is
described. This reaction affords fused polyheterocycles in
moderate to good yields. The transformation begins with Pd-
catalyzed 5-exo-dig cyclization of enynone to form the
donor/donor metal carbene; which then undergoes metathesis
with alkyne followed by electrophilic aromatic substitution.
Carbene mediated cascade reaction is a powerful tool for
building new bonds.1 In particular, transformations that
involve carbene/alkyne metathesis (CAM) have shown high
efficiency in bond formations, which leads to direct
construction of complex molecular frameworks.2-6 The
pioneering work in this area reported by Padwa involves
alkynl-tethered diazo compounds, with silver2a and rhodium
complex2b,2c as catalyst. Later, various metal catalysts,
including nickel,3a,3b ruthenium,3c-3f and copper,4a,4b were
disclosed to promote the corresponding cascade
transformations. On the other hand, the using of other readily
available and relative stable substrates as the initiator, such as,
triazole or hydrazone, instead of diazo compound, is
developed by Gevorgyan,5 May,6a Pla-Quintanaa,6b-6c Zhang
and Bruin6d independently (Scheme 1a). Despite the advances
of these cascade reactions involving CAM, the substrate scope
is still limited, and the development of practicable carbene
precursor with compatible catalytic system would certainly be
in demand.
Scheme 1 Types of metal carbene cascade reactions.
various subsequent reactions such as C-H and X-H insertion,8
cycloaddition/annulation,9 coupling reactions,10 and others,11
to provide the corresponding furan derivatives. Inspired by
these works and as the continuation of our interest in
polycyclic structure construction based on CAM reaction,4
As a reliable and useful non-diazo carbenoid precursor,
enynone has been applied in a wide range of carbene
reactions.7 And the key step in these transformations involved
a transition metal catalyzed 5-exo-dig cyclization to generate
herein, we describe
a novel carbene/alkyne metathesis
cascade reaction with enynone as the carbene precursor. In
comparison with the reported Pd-catalyzed general coupling
reactions of enynone via migratory insertion process by Wang
(Scheme 1b),10a-10c this work is the first example of readily
available palladium complex catalzyed carbene/alkyne
metathesis reaction (Scheme 1c). The 3, 4-disubstituted 2H-
chromene product generated by this cascade reaction is
prevalent in natural products and bioactive molecules.12
the donor/donor carbene intermediate (Scheme 1b, A
).8a Once
formed in situ, the metal carbene intermediate can undergo
a.Key Laboratory of Organic Synthesis of Jiangsu Province; College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123
(P. R. China) E-mail: qiulihua@suda.edu.cn, xinfangxu@suda.edu.cn.
b.State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin
300071, China
† Electronic Supplementary Informaꢀon (ESI) available. CCDC 1545526 (4d). For ESI
and crystallographic data in CIF or other electronic format see
DOI: 10.1039/x0xx00000x
Alkyne-tethered enynone 1a was first prepared according to
known procedure (see Supporting Information for details),
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Table 1 Optimization of the reaction conditionsa
Table 2 Substrates scopea,b
Yield b (%)
Catalyst (x mol%)
Entry
Rh2(OAc)4 (1.0 mol%)
[Rh(COD)OH]2 (2.0 mol%)
Cu(OTf)2 (5.0 mol%)
PPh3AuCl (5.0 mol%)
PPh3AuCl (5.0 mol%) +
AgSbF6 (5.0 mol%)
1
2
3
4
20
30
18
nrc
5
6
7
<5
<5
<5
AgSbF6 (5.0 mol%)
PPh3AuCl (5.0 mol%) + AgBF4
(5.0 mol%)
AgBF4 (5.0 mol%)
8
9
<5
25
37
26
62
57
70
ZnCl2 (20.0 mol%)
Pd(OAc)2 (5.0 mol%)
Pd(PPh3)4 (5.0 mol%)
Pd2(dba)3 (5.0 mol%)
Pd2(dba)3 (5.0 mol%)
Pd2(dba)3 (5.0 mol%)
10
11
12
13d
14e
a The reaction was conducted with 1a (0.2 mmol), catalyst (x mol%) in
b
c
DCE (3.0 mL) at 25 oC under Ar. Isolated yields. Most of 1a was
recovered. The reaction was conducted at 40 oC. 4 Å Molecular sieve
(30 mg) was added as additive. DCE = 1,2-dichloroethane, nr = no
reaction.
d
e
substitutions on the aryl ring, all the substrates gave the
then utilized as model substrate to probe the cascade reaction:
it was mixed with various catalyst (with 1.0-5.0 mol%),
including Rh, Au, Zn and Pd (Table 1, entries 1-12) in 1,2-
dichloroehtane (DCE). Except for PPh3AuCl, which was turned
out no reactivity at all, and majority of the material 1a was
recovered (entry 4). Most of the tested catalysts could
promote the conversion of 1a, although low selectivities were
observed in some cases and the rest of material was
products in moderate to good yields (2a−2k). Interestingly,
two diastereoisomers of the product 2l were obtained, which
arises from restriction of rotation between the two aromatic
planes.13 Meanwhile, the aryl-substituted enynones proceeded
equally well, and leading to the desired products 2m−p in
60−72% yields. For material 1r, which has a "N" linker instead
of "O", although the reaction is quite clean according to the
proton NMR of the crude reaction mixture (see Figure S1 in SI),
however, the product was decomposed into a complex
mixture during the isolation on column chromatography.
When 1s, which has a methylene linker, was applied, although
no reaction occurred in the presence of either Pd(OAc)2 or
Pd2(dba)3, we did observe the product when the reaction was
catalyzed by Rh2(OAc)4, and corresponding product 2s was
obtaiend in 55% yields after 12 hours. In addition, these
reaction conditions were also successfully applied to the
decomposed into a complex mixture (entries 5−8). Lower
reactivity was found with Pd(PPh3)4 (entry 11) compared to
Pd(II)-catalyst (entries 10). Using Pd2(dba)3 as the catalyst led
to a significant improvement of the reaction and 2a was
obtained in 62% isolated yield, which may due to it relatively
low Lewis acidity (or
π-electrophilicity) and weakly
coordination ligands of this catalyst (entry 12). Elevating the
reaction temperature did not provide better result (entry 13)
while introducing 4Å molecular sieve as additive increased the
yield to 70% (entry 14).
unsymmetrical enynone Z-1q, and mono-carbonyl substrate 1t
,
which gave 2q and 2t in 62% and 53% yields, respectively. The
methyl-substituted alkyne (1u) and terminal alkyne (1v) could
not provide the corresponding product and the materials were
decomposed into a complex mixture slowly, which may mainly
due to the lower stability of the in situ generated carbenoid
With the optimized reaction conditions in hand, we went on
to explore substrate scope of this reaction, and the results are
listed in Table 2. The influence of the aryl group, which is
adjacent to the alkyne moiety, was explored first (2a−l).
Regardless of the position or electronic property of the
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Scheme 4 Proposed reaction mechanism.
Scheme 2 Scale up and [4+2] cycloaddition.
reaction was initiated by a palladium-catalyzed 5-exo-dig
cyclization of enynone to form the donor/donor carbenoid
intermediate
and terminated with electrophilic aromatic substitution (EAS
on the newly formed furan ring with the in situ generated
carbenoid intermediate (Scheme 4). However, further
B, followed by carbene/alkyne metathesis (CAM),
)
C
studies are needed to unambiguously establish the reaction
transformation.
In summary, we have developed a palladium-catalyzed novel
carbene/alkyne metathesis (CAM) cascade reaction of alkyne-
tethered enynone, which provides a straightforward approach
for the synthesis of furan fused polyheterocycles in moderate
to high yields. In addition, this reaction not only represents the
first example of CAM reaction promoted by readily available
palladium complex, but also is the only example of the use of
enynone as carbene precursor in intramolecular
carbene/alkyne metathesis cascade transformation. Potential
applications of this strategy for the polycyclic compounds
synthesis are under exploration in our laboratory.
Scheme 3 Control experiments.
intermediate compared to the corresponding aryl stabilized
ones.
To demonstrate the scalability and the practicality of the
current method, a gram scale reaction was carried out, and
1.044 g of 2a was isolated in 61% yield (Scheme 2a). [4+2]
Cycloadditions applying the products from the cascade
reaction were also investigated (Scheme 2b). Either terminal or
internal electron deficient alkynes performed well under
thermal conditions, and generated the corresponding addition
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
products with moderate to good yields (4a−d). The structure of
Support for this research from the National Natural Science
Foundation of China and NSFC of Jiangsu (NSFC21602148,
BK20150315, and 15KJD150004); and the Priority Academic
Program Development (PAPD) of Jiangsu Higher Education
Institutions is gratefully acknowledged.
product 4d was unambiguously determined by single-crystal X-
ray diffraction analysis,14 and the corresponding structure of
could be deduced.
2
To gain insight into the mechanistic details, control
experiments were carried out as shown in scheme 3. Firstly,
the enyone part in the material was removed, and no reaction
occurred with
5 under the standard conditions (Scheme 3a),
Notes and references
which means the transformation was initiated with the
enynone species. To demonstrate that the donor/donor
carbenoid, which was generated from enynone in situ, was
involved in this transformation, two typical carbene reactions,
including C-H insertion and β-H elimination, were designed and
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performed (Scheme 3b and 3c). Two corresponding products
and were obtained in 70% and 55% yields, respectively.
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An
unprecedented
palladium-catalyzed
carbene/alkyne
metathesis reaction of alkyne-tethered enynones is
described, which delivers fused-furans in moderate to good
yields.
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