Tunable Gold(I)-Catalyzed [4 + 3] Cycloaddition for Divergent Synthesis of Furan-Fused N,O-Heterocycles

Article abstract of DOI:10.1021/acs.orglett.9b04312

By choosing suitable ligand-directed gold catalysts, two types of gold-containing all-carbon 1,4-dipoles could be generated selectively from the gold(I)-catalyzed cycloisomerizations of allenyl ketones bearing a cyclopropyl moiety, which undergo [4 + 3] c

Full text of DOI:10.1021/acs.orglett.9b04312

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Letter
Tunable Gold(I)-Catalyzed [4 + 3] Cycloaddition for Divergent
Synthesis of Furan-Fused N,O-Heterocycles
Shouzhi Zhang, Aijie Tang, Panpan Chen, Zhiqiang Zhao, Maozhong Miao,* and Hongjun Ren*
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ABSTRACT: By choosing suitable ligand-directed gold catalysts, two types of gold-containing all-carbon 1,4-dipoles could be
generated selectively from the gold(I)-catalyzed cycloisomerizations of allenyl ketones bearing a cyclopropyl moiety, which undergo
[4 + 3] cycloadditions with nitrones to produce two regiomers of furan-condensed N,O-seven-membered rings in moderate to
excellent yields highly selectively.
Scheme 1. Transition-Metal-Based Approaches to All-
Carbon 1,4-Dipoles and Our Envisaged Strategy toward 1,4-
Dipoles I and II under Gold Catalysis
ntermolecular cycloaddition represents a powerful tool to
Icreate a myriad of functionalized carbocyclic and hetero-
cyclic frameworks in a highly regio- and stereocontrolled
fashion.1 While traditional protocols by applying stable
conjugated 1,3-dipoles to react with unsaturated bonds to
produce cyclic motifs are well documented,2 studies on
utilizing nonclassical all-carbon 1,4-dipoles, a class of highly
reactive variants without a fully conjugated system,3 for
cycloaddition reactions remain a critical challenge and are of
high value in organic chemistry.
Benefiting from the development of the transition-metal
catalysis in organic synthesis,4 a few approaches have been
established to enter the polarized four-carbon units, binding a
relatively strong carbon−metal bond via elaborate design of
substrates.5 For example, in 2007, an elegant work involving
the generation of 1,4-zwitterionic dipoles with a π-allylpalla-
dium moiety from a palladium(0)-catalyzed oxidative addition
into the γ-methylidene-δ-valerolactones and decarboxylation
process was first disclosed by Hayashi6 and co-workers
(Scheme 1, eq 1). Later, vinyl benzoxazinanone derivatives
have also been successfully used as valuable precursors of an
aromatic ring containing 1,4-dipoles undergoing a similar
decarboxylation process.7 The homogeneous gold catalysis has
emerged as a continuously growing field of investigation.8
Owing to the exceptional π-acidity of cationic gold(I)
complexes to activate unsaturated carbon−carbon bonds,
Zhang’s group9 developed the first gold(I)-catalyzed cyclo-
isomerization of 1-(1-alkynyl)cyclopropyl ketones toward
Received: December 1, 2019
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conceptually novel gold-containing all-carbon 1,4-dipoles
(Scheme 1, eq 2). These strategies have offered new
opportunities to trigger the formation of all-carbon 1,4-dipoles
and modulate their reactivity to participate in some cyclo-
addition reactions.10 To the best of our knowledge, the
generation of diverse all-carbon 1,4-dipoles using allenes11 as
well designed precursors by means of π-metal catalysis and
ligand effect is still unknown.
Scheme 3. Scope of the PPh3AuOTf-Catalyzed Reaction for
the Synthesis of 3
a b
,
Allenyl ketones (1) with a highly strained cyclopropylidene
group adjacent at the end of the cumulated double bond are a
subunit of thermally stable, yet activated allenic derivatives.12
The versatile reactivity makes these compounds highly
attractive synthetic building blocks in organic synthesis.
Recently, we13 have developed a regioselective synthesis of
polysubstituted furans from the cycloisomerization/ring open-
ing of allenyl ketones bearing a cyclopropyl moiety with
alcohols, displaying an unprecedented 1,2-gold carbene
transfer reactivity (Scheme 1, eq 3). Our group’s continued
interest in transition-metal-catalyzed transformation of allenyl
ketones prompted us to investigate the potential of these
derivatives as the precursors of two kinds of furan-containing
1,4-dipoles I and II for cycloaddition reactions (Scheme 1, eq
4). As a result, herein we report the gold(I)-catalyzed divergent
synthesis of furan-fused seven-membered N,O-heterocyclic
compounds via the tandem cycloisomerization and formal [4 +
3] cycloaddition of allenyl ketones (1) with various nitrones.
Nitrones have found wide application in 1,3-diploar
cycloadditions for the preparation of a plethora of N,O-
heterocyclic derivatives.14 Thus, they were selected as a
coupling partner for processing cycloadditions with the
envisaged gold-containing all-carbon 1,4-dipoles I or II for
optimization studies. Upon addition of cyclopropyl-tethered
allenyl ketone 1a to a solution of N,α-diphenyl nitrone 2a, 100
mg of 4 Å MS, and 5 mol % of PPh3AuOTf in DCM at room
temperature, a mixture of the anticipated cycloadducts 3a and
4a was obtained in 90% total yield with 9:1 ratio (Scheme 2).
a
The reaction was carried out using 1 (0.2 mmol, 1 equiv) and 2 (0.6
mmol, 3 equiv), 100 mg of 4 Å MS, and 10 mol % of PPh3AuOTf
under N2 atmosphere. Isolated yield of 3; ratio determined by H
NMR analysis of the crude product.
b
1
Nitrones bearing 2-furyl and styryl groups at the α-position, as
well as those with different substituents on the N-phenyl rings,
all worked well in this reaction, furnishing their respective
products (3h−l) with high yields and excellent regioselectiv-
ities. Subsequently, the capacity of different cyclopropyl-
tethered allenyl ketones 1 was defined. A benzene ring with
4-Br, 4-Me, 4-OMe, and 4-acetyl groups, as well as 2-naphthyl
and 2-thienyl, were well tolerated at the R1 position, delivering
the desired product (3m−s) in modest to good yields with
overwhelming selectivities (rr > 20:1). Nevertheless, low yield
and poor regioselectivity (39%, rr = 2:1) were obtained in the
case of the isopropyl-substituted substrate (3t). Varying the
substituents of aromatic rings at the R2 position, the reaction
proceeded smoothly to afford 3u−x in 47−72% yields with
high regioselectivities.
Scheme 2. Initial Observation and Optimized Reaction
Conditions for Selectively Producing 3a and 4a
The scope of the selective cycloaddition reaction for the
synthesis of 4 is demonstrated in Scheme 4. Likewise, a wide
range of nitrones were employed to react with cyclopropyl-
tethered allene ketone 1a, the reaction performed well to afford
4a−k in modest to high yields with well-controlled
regioselectivity. Nitrones with electron-deficient substituents
at α-phenyl rings provided the corresponding cycloadducts
(4b−d) in higher yields than electron-rich ones (4e−g). N-
Benzyl and various substituted N-aromatic nitrones were
compatible, giving the cycloadducts 4h−k in acceptable yields.
The substrate scope of allenyl ketones 1 was then examined. It
was found that both electron-deficient and electron-rich groups
on the benzene ring, as well as 2-naphthyl, 2-thienyl, isopropyl,
and 4-cyclohexenyl at the R1 position, were compatible,
furnishing the targeted molecules (4l−s) in high yields (up to
93%) and regioselectivities (rr > 15:1). Various aromatic rings
could be properly installed at the R2 position to afford the
We subsequently carried out a systematic optimization (for
details, see Table S1 and Table S2 in the Supporting
Information). Two catalytic protocols for the selectively
producing 3a (90% yield, rr = 45:1) and 4a (67% yield, rr =
1:24) were established by employing different gold(I) catalysts
(Scheme 2).
Upon the identification of a set of reaction conditions, we
turned to explore the generality of the cycloaddition between
allenyl ketones 1 and a variety of nitrones 2 for the selective
formation of cycloadducts 3 (Scheme 3). Neither electron-
donating nor electron-withdrawing substituents on the α-
phenyl rings of nitrones affected the efficiency of the
cycloaddition, furnishing the corresponding cycloadducts
3a−g in good yields, albeit a lower regioselectivity was found
in the case of strong electron-withdrawing groups (3f and 3g).
B
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a gram scale, affording 1.12 g of 3a and 1.10 g of 4a after
recrystallization. Both 3a and 4a could undergo chemoselective
hydrogenation by treatment with H2/Raney Ni to produce 5
and 7 in high yields. In addition, 3a and 4a also underwent [4
+ 2] cyclizations with benzyne generated from o-dibromo-
benzene/n-BuLi under −20 °C to solely afford 6 and 8 in high
yields with excellent stereoselectivities. Furthermore, the
attempt of asymmetric reactions by employing (R)-BINAP as
the ligand was made. The reaction provided the desired 3e in
25% yield (rr = 3:1) and 0% ee. On contrast, the reaction
rendered 17% enantiomeric excesses with a synthetically useful
yield in the case of the formation of 4b, indicating the potential
of developing an enantioselective process of synthetic value.
To gain some mechanistic insights into these trans-
formations, control experiments were conducted (Scheme 6).
Scheme 4. Scope of the t-BuXPhosAuCl/AgSbF6-Catalyzed
Reaction for the Synthesis of 4
a b
,
Scheme 6. Mechanistic Investigations
a
The reaction was carried out using 1 (0.24 mmol, 1.2 equiv), 2 (0.2
mmol, 1 equiv), and 100 mg of 4 Å MS, with a combination of 2 mol
% of t-BuXPhosAuCl and 15 mol % of AgSbF6 in TCE at 120 °C
b
1
under N2 atmosphere. Isolated yield of 4; ratio determined by H
NMR analysis of the crude product.
desired compounds (4t−w) in good yields with excellent
regioselectivity.
To demonstrate the scalabilities and synthetic utilities of the
two reactions, several transformations were performed. As
depicted in Scheme 5, the reactions could be easily enlarged to
Scheme 5. Gram-Scale Synthesis, Synthetic Application, and
Attempt of Asymmetric Catalysis
First, allenyl ketones 1n and 1o were subjected to react with
nitrone 2e under two established sets of conditions. In the
presence of Ph3PAuOTf (10 mol %) or a combination of t-
BuXPhosAuCl (2 mol %) and AgSbF6 (15 mol %), both
reactions cleanly led to the formation of substituted furans
10a−b with distinct efficiency, yet the desired cycloadducts
were not detected (Scheme 6, eq A). These results clearly
suggest that the high strained cyclopropyl moiety plays
important roles in these reactions. Then, the furan-fused
cyclobutene 9 was employed to react with 2e under two types
of gold catalysts. To our surprise, the cycloadduct 4r involving
the 1,4-dipole II was solely obtained in 57% and 62% yields
under these conditions, and the regiomer 3t was not formed.
Moreover, the treatment of substrate 1o with 10 mol % of
Ph3PAuOTf in the absence of nitrone led to quite slow
transformation to furan-fused cyclobutene intermediate 9
(Scheme 6, eq B). These results indicate that the furan-fused
cyclobutene may be a key intermediate in the formation of the
cycloadduct 4, and the cationic gold(I) catalyst dominates the
C
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ring opening of furan-fused cyclobutene to generate 1,4-dipole
II. The rate of formation of furan-fused cyclobutene might be
the key point in selectively producing compounds 4 in
reactions involving cyclopropyl-tethered allenyl ketones 1 and
nitrones 2 catalyzed by t-BuXPhosAuCl (2 mol %) and AgSbF6
(15 mol %). Finally, we noticed that the reactions gave the
different ratios of 3a and 4a in the presence of different π-metal
catalysts in DCM at room temperature. In addition, the
mixture of 3a and 4a did not decompose in the combination of
t-BuXPhosAuCl (2 mol %) and AgSbF6 (15 mol %) at 120 °C
(Scheme 6, eq C). Marshall,15 Hashmi,16 and Gevorgyan17
have presented fruitful results in transition-metal (Rh, Ag, Pd,
Au, Cu, etc.) catalyzed cycloisomerization of allenyl ketones
which have been served as cyclic metal carbene precursors.18
Thus, it is reasonable to assume that the reaction of 1a
catalyzed by π-metals would afford spirocyclic oxonium/
carbene intermediates Int-A/Int-B. The phosphine ligand-
directed gold(I) may promote the ring opening of spirocyclic
oxonium Int-A to form 1,4-dipole I, while AgSbF6 and AuCl
etc. promote a fast ring expansion to deliver furan-fused
cyclobutene and its further transformations.
It is noted that an alternative pathway via direct SN2-type
nucleophilic attack of nitrone’s oxygen atom on the cyclo-
propyl ring of Int-A followed by ring-closure reaction to afford
the [4 + 3] cycloadduct 314d is also highly possible. When the
ligand-free catalysts such as AgSbF6, AuCl, or combined
catalytic systems, etc. were applied, the metal-carbene
resonance Int-B might undergo a fast ring-expansion reaction
followed by elimination of [M] to provide the key intermediate
furan-fused cyclobutene Int-C. In the case of using t-
BuXPhosAuSbF6 and AgSbF6 as cocatalysts, the cationic gold
species might dominantly reactivate to the highly strained C−
C double bond of Int-C to form Int-D, which would transform
to the key cyclic gold carbene Int-E and its spirocyclic
oxonium structure Int-F by ring contraction. Subsequently,
intermediate Int-F underwent ring-opening to generate a
regio-switched gold-containing all-carbon 1,4-dipole II (Path
B), which could cyclize with nitrone 2 to produce the
alternative 4 via TS-2. Similarly, a SN2-type nucleophilic attack
of Int-F with nitrone 2 followed by ring closure might also
occur to furnish the cycloadduct 4.
In summary, the gold-catalyzed tandemn cycloisomeriza-
tions and formal [4 + 3] cycloadditions of allenyl ketones
bearing a cyclopropyl moiety with nitrones were developed to
provide a diverse range of furan-fused N,O-heterocycles in very
high regio- and stereoselectivity. Furan derivatives not only
represent versatile building blocks in organic synthesis but also
have been frequently found as key skeletons in many bioactive
natural products, pharmaceutical substances, and functional
materials. Taking advantage of this strategy, studies to address
the further applications of these novel dipoles in gold catalysis
and the development of asymmetric variants of these
annulations, as well as their application in the synthesis of
biologically relevant molecules, are currently underway in our
laboratory.
Although the full mechanistic details of these trans-
formations remain to be elucidated, plausible mechanisms for
the reactions are outlined in Scheme 7. Electrophilic [M]
Scheme 7. Proposed Reaction Pathways for the Cyclization
of Allenyl Ketones Bearing a Cyclopropyl Moiety 1
Catalyzed by π-Metals
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04312.
Experimental procedures and copies of 1H and 13C
NMR spectra for all new compounds (PDF)
Accession Codes
CCDC 1962635−1962638 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
activation of the electron-rich double bond in allenone moiety
1 could induce a nucleophilic-type cyclization that would lead
to the formation of the spirocyclic oxonium/carbene forms
Int-A/Int-B. When PPh3AuOTf was employed, the ring
opening of the spiro-cyclopropyl ring that attached at Int-A
might yield a gold-containing all-carbon 1,4-dipole I5,9a (Path
A). The following intermolecular [4 + 3] cycloaddition of 1,4-
dipole I with nitrone 2 via TS-1 might give the cycloadduct 3.
Maozhong Miao − Zhejiang Sci-Tech University,
Hangzhou, P. R. China; orcid.org/0000-0001-6777-
7189; Email: mmzok@zstu.edu.cn
Hongjun Ren − Zhejiang Sci-Tech University, Hangzhou,
P. R. China, and Taizhou University, Taizhou, P. R.
China; orcid.org/0000-0002-4506-1961;
Email: renhj@tzc.edu.cn
D
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Other Authors
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Shouzhi Zhang − Zhejiang Sci-Tech University,
Hangzhou, P. R. China
Aijie Tang − Zhejiang Sci-Tech University, Hangzhou, P.
R. China
Panpan Chen − Zhejiang Sci-Tech University, Hangzhou,
P. R. China
Zhiqiang Zhao − Zhejiang Sci-Tech University,
Hangzhou, P. R. China
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the Natural Science Foundation of Zhejiang
Province (Grant No. LY19B020017) and the Fundamental
Research Funds of Zhejiang Sci-Tech University (Grant No.
2019Q064) and the Zhejiang Provincial Top Key Academic
Discipline of Chemical Engineering and Technology of
Zhejiang Sci-Tech University for financial support.
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