Gold(III)-Catalyzed Regioselective Oxidation/Cycloisomerization of Diynes: An Approach to Fused Furan Derivatives

Article abstract of DOI:10.1021/acs.orglett.8b01915

The first gold(III)-catalyzed regioselective oxidation/cycloisomerization of diynes 1 with pyridine N-oxide as the oxidant was developed, providing a range of synthetically valuable and useful fused furan derivatives 3 in moderate to good yields. Control experiments and the confirmation structure of minor products 5 suggest that this chemistry was a concerted gold(III)-catalyzed oxidation/S_N2′-type addition/cyclization process via a β-gold vinyloxypyridinium intermediate and a putative vinyl cation intermediate.

Full text of DOI:10.1021/acs.orglett.8b01915

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Gold(III)-Catalyzed Regioselective Oxidation/Cycloisomerization of
Diynes: An Approach to Fused Furan Derivatives
Jian Li, Hong-Wen Xing, Fang Yang, Zi-Sheng Chen,* and Kegong Ji*
College of Chemistry and Pharmacy, Northwest A&F University; Shaanxi Key Laboratory of Natural Products & Chemical Biology,
3 Taicheng Road, Yangling, 712100, Shaanxi, P. R. China
S
* Supporting Information
ABSTRACT: The first gold(III)-catalyzed regioselective oxidation/
cycloisomerization of diynes 1 with pyridine N-oxide as the oxidant
was developed, providing a range of synthetically valuable and useful
fused furan derivatives 3 in moderate to good yields. Control
experiments and the confirmation structure of minor products 5
suggest that this chemistry was a concerted gold(III)-catalyzed
oxidation/SN2′-type addition/cyclization process via a β-gold vinyl-
oxypyridinium intermediate and a putative vinyl cation intermediate.
Scheme 1. (A) Gold(I)-Catalyzed Selective Oxidation of
Alkynes; (B) Our Design: Gold(III)-Catalyzed
Regioselective Oxidation and Cycloisomerization of
Alkyne−Ynone; (C) Natural Products Containing the Motif
of Fused-Furan Core
he oxidation of alkynes by using intermolecular pyridine/
1
Tquinoline N-oxides as oxidants has become a valuable
synthetic strategy owing to the efficient and expedient access to
α-oxo gold carbene/carbenoid intermediates in the presence of
a gold(I) catalyst.2 Due to the strong π-philicity nature of
gold(I), a range of functional structures of significant synthetic
methods have been developed.3−9 To date, most of the
reactions reported have been proposed to proceed by the
intra-4 or intermolecular5 trapping of the α-oxo gold carbene
intermediates (Scheme 1A). However, in the oxidation of
alkynes using N-oxide as the oxidant, gold(III) is a less efficient
catalyst, because of their strong oxophilicity nature. For a more
useful oxidation of alkynes approach and the development of a
gold catalyst, as shown in Scheme 1B, our design anticipated
that with alkyne−ynone substrates 1 and the π-philicity/
oxophilicity nature of gold(III) as the catalyst, a novel
noncarbene model of β-gold(III) vinyloxypyridinium B could
be site selectively generated upon oxidation of the ynone C−C
triple bond. Subsequently, the β-gold(III) vinyloxypyridinium
B would be attacked by an appropriately tethered internal
alkyne via concerted SN2′ type addition3h,4f,h,10 and cyclo-
isomerization to afford furan derivatives 3, which is an
important motif in natural products,11 such as Granaticin
A,11a Bhimamycin B,11b and Hibiscone C11c (Scheme 1C).
Interestingly, the easier oxidation process12 with a simple C−C
triple bond by using gold(I) catalysts was regioselectively
limited in this alkyne−ynone system (Scheme 1B). As part of
our ongoing work in the field of gold catalysis,4j−l,7 we reported
herein the first gold(III)-catalyzed regioselective oxidtion/
cycloisomerization of diynes6−8 to fused furan derivatives from
more flexible and readily accessible systems (Scheme 1B).
Notably the reaction, if developed, would offer novel and rapid
access to valuable fused cyclic products.
Received: June 20, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01915
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Table 1. Initial Discovery of Gold(III)-Catalyzed Selective Oxidation/Cycloisomerization of Diyne 1a and Screening of
a
Reaction Conditions
b
entry
2
catalyst
additive (equiv)
temp (°C)
t (h)
yield (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
KAuCl4·2H2O
KAuCl4·2H2O
KAuCl4·2H2O
KAuCl4·2H2O
KAuCl4·2H2O
KAuCl4·2H2O
AuCl3
−
−
−
−
−
−
−
−
−
−
−
−
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
50
50
50
50
50
6.5
6.5
6.5
6.5
6.5
6.5
48
48
48
48
6.5
3.5
3.5
3.5
3.5
3.5
57
36
24
messy
22
messy
43
22
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
PicAuCl2
9
L1Au(III)Cl
L2Au(III)Cl3
40
10
11
12
13
14
15
16
trace
NR
64
74
62
c
IPrAuNTf2
KAuCl4·2H2O
KAuCl4·2H2O
KAuCl4·2H2O
KAuCl4·2H2O
KAuCl4·2H2O
d
e
MgSO4 (0.4)
MgSO4 (0.4)
MgSO4 (0.4)
MgSO4 (0.4)
b
d
d
d
f
g
63
58
h
a
1
Reaction condition: [1a] = 0.05 M and 1.2 equiv of the oxidant 2. Estimated by H NMR spectroscopy using diethyl phthalate as the internal
reference. 5 mol % catalyst. 1.35 equiv of oxidant 2a. Reactions performed on 0.2 mmol scale; 66% isolated yield of 3a after purification by
column chromatography. 1,2-Dichloromethane as the solvent, [1a] = 0.1 M. Chlorobenzene as the solvent. Toluene as the solvent.
c
d
e
f
g
h
t
At the outset, we employed the tethered alkyne−ynone 1a,
for reaction discovery and condition optimization, some results
of which are shown in Table 1. Initially, hydrated KAuCl4 (10
mol %) was chosen as the catalyst, and 2,6-dichloropyridine N-
oxide (2a, 1.2 equiv), as the oxidant; the reaction was carried
out in dichloromethane (DCM) at room temperature for 6.5 h.
To our delight, the desired tetrahydropyranone-fused furan 3a
was indeed formed in 57% NMR yield (entry 1). Screening of
various other pyridine/quinoline N-oxides (entries 2−6)
revealed that sterically hindered oxidants derived from the
electron-deficient pyridine ring, i.e., 2,6-dibromopyridine N-
oxide (2b, entry 2), was effective, but was still substantially
inferior to even more electron-deficient 2,6-dichloropyridine
N-oxide 2a. A range of other gold catalysts such as AuCl3
(entry 7), PicAuCl2 (entry 8), L1AuCl (entry 9), and L2AuCl2
(entry 10) were invetigated, affording less than 45% yield of
3a, even after a longer time. Gold(I) catalysts were also
investigated, and the electron-rich IPr carbene was employed
as the ligand, as it was previously proven to be highly effective
in promoting cyclopropanation of α-oxo gold(I) carbenes,
which were generated from ynones, to C−C double bonds.4f
With AgNTf2 (5 mol %) as the chloride scanvenger and 2a
(1.2 equiv) and other N-oxides as the oxidants (for details, see
Supporting Information (SI)), the reaction was carried out in
dichloromethane (DCM) at room temperature for 6.5 h.
Unfortunately, no reaction was observed from crude NMR
without consuming 1a (entry 11). Screening of other cationic
gold(I) complexes derived from typical ligands such as Ph3P,
Cy3P, Phosphite, X-Phos, and Me4 BuXPhos revealed that
these cationic gold(I) complexes were ineffective, which
indicated that the reaction required stronger Lewis acidity
regarding Au(III)13 as a smooth trigger by activating the ynone
group (for details, see SI). With KAuCl4 (10 mol %), the
reaction was carried out at 50 °C in a sealed tube for 3.5 h, and
a slightly higher yield was obtained, along with gold
precipitation (entry 12). MgSO4 (0.4 equiv) was chosen as
an additive to increase the desired product 3a to 74% yield
without observing double oxidation product 4-acetyl-5-
benzoylpyranone 4a, which indicated that the selective
oxidation−cycloisomerization was a concerted process (entry
13). Other additives, such as molecular sieves, bases, and Lewis
acids were ineffective (for details, see SI). The effect of the
solvents, such as, 1, 2-dichloroethane, PhCl, and toluene, were
also considered, but no better results were observed (entries
14−16). Other oxidants, such as triphenylphosphine oxide and
diphenyl sulfoxide, were also tested, but no good results were
observed (for details, see SI).
With the optimal conditions (Table 1, entry 13) in hand, the
reaction scope was examined. As shown in Scheme 2, tethered
alkyne−ynones 1b−1d possessing an aliphatic R group at the
end of the carbonyl group reacted as expected, despite
exhibiting moderate yields. Furthermore, the aldehyde
substrate, such as 1e with a hydrogen R group, proceeded
smoothly to provide corresponding product 3e in an
acceptable yield.14 Aromatic R groups were also investigated,
such as 1f−1k; various electron-donating and -withdrawing
B
DOI: 10.1021/acs.orglett.8b01915
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a b
,
Scheme 2. Reaction Scope
a
b
The reactions were run in a sealed tube at 50 °C in DCM, and the substrate concentration was 0.05 M. Yields of isolated products are reported.
c
d
15% catalyst was used. [M] = 0.1 M; 12% catalyst was used.
groups installed on benzene ring were also readily tolerated.
Moreover, considering synthetically useful transformations,
tethered alkyne−ynones such as 1y−1ad with different
aliphatic substitutions were also investigated and afforded the
desired products 3y−3ad in moderate to good yield. A benzyl
and an allyl group were tolerated, and their π bonds did not
noticeably interfere with the desired cycloisomerization, likely
due to the formation of larger rings and, hence, slower
cyclization kinetics. On the other hand, a simple chloro,
OTBDPS substituted and chiral L-menthol and bulky β-
sitosterol substituted aliphatic linker led to desired products
3y−3z and 3ac−3ad in good yield.
The relative configuration of the product 3k was unambigu-
ously assigned by X-ray crystallography (CCDC 1816724).15
Moreover, an interesting case with a para-OMe substituted
benzene R group was transferred to afford the desired 3l in
57% yield, along with 7% of 5-hydroxy-7-methoxy-10-phenyl-
1H-benzo[g]isochromen-4(3H)-one 5l. This phenomenon was
also observed with a furan and indole R groups, such as
substrates 1m and 1n; moderate yields of major tetrahy-
dropyranone-fused furans 3m−n were obtained separately, and
around 10% yields of minor products 5m−n were also
accessed. The relative configuration of the minor product 5m
was unambiguously assigned by X-ray crystallography (CCDC
1816725), which suggested that the minor products 5 might be
formed via a selective oxidation/Friedel−Crafts cycloisomeri-
zation and rearrangement process, implying the existence of a
putative vinyl cation intermediate.7 Tethered alkyne−ynone 1o
possessing a heteroaromatic R group, such as 2-thienyl,
proceeded smoothly to provide corresponding product 3o in
77% yield. The steric effect of the R″ group was also
considered, such as 1p; a methyl was readily tolerated at the
propargyl position. Other tethered alkyne−ynones 1q−1x by
installing a methyl R group at the end of carbonyl group,
possessing R′ groups at the end of terminal alkyne, worked
well. The reaction was tolerant of various electron-rich and
-deficient aromatic, heteroaromatic, and aliphatic R′ groups.
Furthermore, we attempted to extend the chemistry to the
all-carbon counterpart of 1a, i.e., 9-phenylnona-3,8-diyn-2-one
1ae. As shown in eq 1, the desired cyclohexanone-fused furan
3ae was formed in 57% yield after 11 h and 23% yield of 1ae
was recovered, indicating that all-carbon substrate 1ae is less
reactive than the oxygen-containing substrate 1a.15
In order to gather additional experimental evidence for the
mechanism, we examined the gold(III)-catalyzed reaction of
the authentic diazo carbonyl species 64f as shown in Scheme 3,
C
DOI: 10.1021/acs.orglett.8b01915
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Organic Letters
Letter
distal end of ynone to give β-gold(III) vinyloxypyridinium B.
(ii) The internal tethered alkyne group as a π-electron
nucleophile attacks β-gold(III) vinyloxypyridinium B inter-
mediate to drive the 2,6-dichloropydine away via SN2′-type
addition, resulting in the formation of a putative vinyl cation
intermediate C. (iii) Then, the active vinyl cation intermediate
C is trapped by the internal carbonyl group to give a more
stable oxygenium-bridged intermediate D, which is rapidly
isomerized to furan derivative 3 and releases the gold complex.
(iv) Alternatively, if R groups are electron-rich aryl groups like
p-methoxybenzene, furan, and indole, the active vinyl cation
intermediate C′ may be trapped by a rich electron site of aryl
groups to give the spiro-oxonium intermediate E. (v) The
spiro-oxonium intermediate E is then transferred to ethenone
intermediate F, where a gold complex promotes the cleavage of
the C−C bond between the carbonyl and spiro carbon, and
then ethenone intermediate F is isomerized to 5-hydroxy-1H-
benzo[g]isochromen-4(3H)-one 5 via gold-promoted Friedel−
Crafts cyclization.
Scheme 3. Control Experiments
The synthetic utility of the tetrahydropyranone-fused furan
products were examined by using 3a as an illustrative example.
Under standard aldol-condensation conditions, it is transferred
to enone product 10a in 72% yield (Scheme 5). Its
where the desired tetrahydropyranone-fused furan 3e was not
observed and only trace amount (<2%) of 5e was observed.
We also carried out 3a at a large scale (1 mmol) with an excess
of N-oxide 2a (2.5 equiv), where the double oxidation product
4a7 was not observed and the desired 3a was isolated in 65%
yield. 5-(Cinnamyloxy)pent-3-yn-2-one 74f,16 was also tested
under standard conditions, but no desired gold carbenecyclo-
propanation product 8 and cycloisomerization product 9 was
observed.
Scheme 5. Transformations of 3a
These control experiments implied that the pure α-oxo gold
carbene might not be the true reactive intermediate in the
reaction, indicating that the β-gold(III)vinyloxypyridinium B
was the more reasonable intermediate. Moreover, we also
carried out the reaction in the presence of H2O without adding
N-oxide 2a; however, no reaction was observed. The reaction
was also attempted in the presence of H2O18, and no O18
labeled product 3a′ was detected from HRMS, indicating that
the new oxygen of 3a was from the N-oxidant 2a (for more
details, see SI-7.2).
On the basis of the above observations, we propose the
following plausible mechanisms for this transformation
(Scheme 4). (i) Gold(III) first coordinates selectively with
C−C triple bonds and the carbonyl group13c in the alkyne−
ynone system, where the N-oxide site selectively attacks the
condensation with hydramine leads to 12a in good yield.
The tetrahydropyranone-fused furan 3a can be easily function-
alized to construct 11a and 13a in moderate to excellent yield
via a [4 + 2] cycloaddition with the C−C triple bond and
reduction with NaBH4.
Scheme 4. Proposed Mechanism
We have realized the first example of gold(III)-catalyzed
tandem selective oxidation−cycloisomerization of diynes 1
with external pyridine N-oxide via a novel noncarbene model
to synthesize tetrahydropyranone-fused furans 3. The reaction
tolerates hydrogen atom as well as aryl and aliphatic
substitutions, and reasonable yields of 3 are obtained in
these instances. Moreover, the chemistry also extends to the
all-carbon counterpart of 1a, and the desired cyclohexanone-
fused furan 3ae was obtained in moderate yield. Control
experiments and the confirmation structure of minor products
5 suggest that this chemistry is a concerted gold(III)-catalyzed
oxidation/SN2′-type addition/cyclization process via a β-
gold(III) vinyloxypyridinium intermediate and a putative
vinyl cation intermediate. Meanwhile, the tetrahydropyra-
D
DOI: 10.1021/acs.orglett.8b01915
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01915.
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Detailed condition investigations, experimental proce-
dures, compound characterization, and X-ray diffraction
data for 3k and 5m (PDF)
Accession Codes
CCDC 1816724−1816725 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.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jikegong@nwsuaf.edu.cn.
*E-mail: chenzsh@nwsuaf.edu.cn.
ORCID
Zi-Sheng Chen: 0000-0001-8778-8889
Kegong Ji: 0000-0001-5707-894X
Notes
(10) Xu, Z.; Chen, H.; Wang, Z.; Ying, A.; Zhang, L. J. Am. Chem.
Soc. 2016, 138, 5515−5518.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We are grateful for the financial support from National Natural
Science Foundation of China (NSF-21502150, 21702170) and
Natural Science Foundation of Shaanxi (2018JQ2072) and the
Youth Training Programme of Northwest A&F University
(Nos. 2452016006, 2452017034)
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E
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