A gold-catalyzed cycloisomerization/aerobic oxidation cascade strategy for 2-aryl indenones from 1,5-enynes

Article abstract of DOI:10.1039/c8ob02582g

A unique gold(i)-catalyzed 5-endo-dig cyclization/aerobic oxidation cascade strategy from 1,5-enyne substrates with molecular oxygen as the oxidant to yield the indenone was described. The reaction mechanism was studied by heavy atom labelling and some related experiments. This method was applied to the formal total synthesis of isoprekinamycin.

Full text of DOI:10.1039/c8ob02582g

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
A gold-catalyzed cycloisomerization/aerobic
oxidation cascade strategy for 2-aryl indenones
from 1,5-enynes†
Cite this: Org. Biomol. Chem., 2018,
16, 9147
Received 17th October 2018,
Accepted 14th November 2018
Jia Guo,‡a,b Xiaoshi Peng,‡a,b Xiaoyu Wang,a,b Fukai Xie,a,b,c Xinhang Zhang,a,b,c
DOI: 10.1039/c8ob02582g
Guoduan Liang,a,b,c Zenghui Sun,a,b,c Yongxiang Liu, a,b,c Maosheng Chenga,b and
a
Yang Liu
*
rsc.li/obc
A
unique gold(I)-catalyzed 5-endo-dig cyclization/aerobic oxi- dioxygen had drawn much attention,7 and the range of tran-
dation cascade strategy from 1,5-enyne substrates with molecular sition-metal catalysts compatible with aerobic oxidation were
oxygen as the oxidant to yield the indenone was described. The extended to gold. Recently some exciting breakthroughs in the
reaction mechanism was studied by heavy atom labelling and combination of gold catalysts and dioxygen have been discov-
some related experiments. This method was applied to the formal ered, such as the oxidation of vinyl–gold complexes into alde-
total synthesis of isoprekinamycin.
hydes by synergistic Au/Fe catalysts and dioxygen,8 the autoxi-
dation of electron-rich alkenes into aldehydes by gold(I) cata-
lysts and dioxygen9 and the reaction of Au-bound cationic
bicyclo[3.2.0]-heptane with a triplet oxygen to form a metallo-
radical through a single electron transfer from Au(I) to O2.10
During the course of our research in developing a gold-cata-
lyzed cascade cyclization strategy to carbocycles,11 we observed
different cyclization paths of the substituted 1,5-enynes with
an electron-rich enol ether. In previous studies, we disclosed a
gold(I)-catalyzed alkyne alkoxylation/tandem cyclization strat-
egy of 1,5-enynes to afford naphthalenes.11a Herein, we report
a distinct pathway of the same 1,5-enynes to produce inde-
nones via a gold-catalyzed 5-endo-dig cyclization/aerobic oxi-
dation cascade strategy (Scheme 1).
Indenones or their corresponding reductive derivatives inda-
nones are important carbocycles that serve as valuable skel-
etons in many biologically active compounds and synthetic
drugs,1 such as donepezil, mukagolactone, indacrinone,
MJ-II-38, pauciflorol
F
and isoprekinamycin (Fig. 1).
Furthermore, indenone derivatives are useful synthetic precur-
sors to steroids and some drugs.2 Therefore, the preparation of
indenones has received considerable attention. Different
metal-catalyzed routes for efficient preparation of indenones
from various starting materials have been developed in the
past decades.3 Recently, Hashmi and co-workers developed a
gold-catalyzed unprecedented oxidative cyclization of diynes to
give this type of product.4
Gold-catalyzed cycloisomerization of 1,5- and 1,6-enynes is
one of the most important strategies for forming functiona-
lized carbocyclic frameworks.5 However, in the presence of
organic oxidants, most enynes failed to produce oxidative pro-
ducts. Recently a new type of gold(I)-catalyzed oxidative cycliza-
tion of 1,5-enynes to indanones and indenes mediated by
8-methylquinoline N-oxide was discovered by Liu’s group.6
As an ideal oxidant in transition metal-catalyzed oxidation,
We tested our proposal as shown in Scheme 1 by subjecting
1,5-enyne substrate 1 (Table 1) with Ph3PAuCl/AgBF4 in
toluene under an N2 atmosphere. The 5-endo-dig cyclization
product 2 could be isolated with excellent yield. Then indene 2
was exposed to air to observe the oxidation. To our delight,
aKey Laboratory of Structure-Based Drug Design and Discovery
(Shenyang Pharmaceutical University), Ministry of Education, Shenyang 110016,
P. R. China. E-mail: yongxiang.liu@syphu.edu.cn, mscheng@syphu.edu.cn
bInstitute of Drug Research in Medicine Capital of China, Benxi, 117000, P. R. China
cWuya College of Innovation, Shenyang Pharmaceutical University,
Shenyang 110016, P. R. China
†Electronic supplementary information (ESI) available: Detailed condition
screening, experimental procedures and spectra. CCDC 1451285. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
c8ob02582g
Fig. 1 Indenone and indanone-containing biologically active molecules
‡These authors contributed equally.
and drugs.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 9147–9151 | 9147

View Article Online
Communication
Organic & Biomolecular Chemistry
entry 10). HAuCl4 could catalyze the cascade cyclization with a
yield of 10%, which was very messy (Table 1, entry 11). In
order to exclude the possibility that a trace amount of acid
catalyzed the reactions, the same amount of HNTf2 itself was
tested and a smaller amount of product 3 was produced with a
messy reaction profile (Table 1, entry 12).
Next the scope of the transformation was investigated
under the optimized conditions (Scheme 2). The reaction with
the substrates bearing both electron-donating and withdraw-
ing groups on both aryl rings proceeded smoothly in moderate
to good yields (Scheme 2, 3a–3o). However, naphthalene-con-
taining products could only be obtained with lower yields
(Scheme 2, 3p–3r). Terminal alkyne and alkyl and silyl substi-
tuted alkyne substrates could not participate in this reaction
under the standard conditions. Interestingly, Liu and co-
workers reported a copper-catalyzed oxidative cyclization of
1,5-enynes and C–C bond cleavage to generate 3-formyl-1-
indenones,3f whose structures were similar to our products.
The structures of our products were determined by comparing
our products with these reported compounds and further
confirmed by a single crystal X-ray diffraction of 3l (Fig. 2).
Scheme 1 Competitive cyclization paths of 1,5-enynes.
Table 1 The screening of reaction conditions
Entry
Catalyst
Additive
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
Ph3PAuBF4
Ph3PAuBF4
Ph3PAuBF4
Ph3PAuBF4
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuNTf2
[(IPr)AuCl]
Ph3PAuNTf2
HAuCl4
—
—
—
—
Dioxane
DCE
THF
2 (65)
2 (80)
2 (86)
3 (65)
—
3 (51)
3 (60)
3 (75)
3 (72)
3 (55)b
2 (10)
3 (15)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
—
AgSbF6
AgOTf
—
AgNTf2
—
9
10
11
12
—
—
HNTf2
a Average isolated yield of at least two runs. b Performed with 5 mol%
Ph3PAuNTf2.
indenone 3 was detected in 30% yield with 60% of indene 2
remaining after one week.
In order to improve the yield of indenone 3, we performed
an intensive screening of optimal conditions to realize these
two transformations in one pot (Table 1). First we set about
investigating solvent effects. Among the tested solvents, only
toluene allowed for the formation of indenone 3. The rest of
the solvents would result in indene 2 in high yield even under
an O2 atmosphere (Table 1, entries 1–4). The influences of
counterions on the catalyst were examined by combining
Ph3PAuCl with several silver salts or using commercially avail-
able catalysts (Table 1, entries 5–8) and Ph3PAuNTf2 afforded
the best yield. Then a screening of different ligands at the
Au-center was carried out. Interestingly, a slight decrease in
yield was observed when mixing [(IPr)AuCl] with silver salts
resulting in the discovery that the combination of the [(IPr)
AuCl] precatalyst [IPr = 1,3-bis(diisopropylphenyl)imidazole-2-
ylidene] (10 mol%) and silver trifluoromethanesulfonate
(10 mol%) was almost the same as Ph3PAuNTf2, yielding the
product in 72% isolated yield (Table 1, entry 9). Decreasing the
Scheme 2 Scope of gold-catalyzed cascade cyclization. a Isolated
catalyst loading to 5 mol% reduced the yield by 20% (Table 1, yields.b Performed for 20 h.
9148 | Org. Biomol. Chem., 2018, 16, 9147–9151
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Communication
Fig. 2 Single crystal X-ray diffraction of 3o.
To investigate the source of O atoms in carbonyl groups, we
performed the reaction in the presence of 18O2 or 18O2/H2O,12
employing 1i as a substrate (Scheme 3). Interestingly, the pro-
ducts 3i-1 (89%) and 3i-2 (11%) were detected under an 18O2
atmosphere assisted with LC-MS. A control experiment by sub-
jecting the isolated intermediate 2i to the standard conditions
under an 18O2 atmosphere resulting in the isolation of the pro-
ducts 3i-1 and 3i-2 ruled out the possibility of incorporation of
the 18O into an aldehyde after cycloisomerization. However, in
the presence of 18O2/H2O or H2O, no 18O atom was incorpor-
ated into the product, and only the product 4i derived from
the hydrolysis and isomerization of the corresponding cyclo-
isomerization product was isolated. However, 4i could not be
transformed into the desired product 3i under the standard
conditions. These results suggested that the ketone group in 3i
was not derived from the oxidation of the benzylic C–H bond
of 4i.
To gain more insight into the reaction mechanism, the iso-
lated indene intermediate 2 in the screening of conditions was
subjected to the optimal conditions and the isolation of inde-
none 3 indicated that the indene 2 was possibly the key inter-
mediate in the transformation (Scheme 4, eqn (1)). A decrease
in the temperature to 25 °C would result in lower yield
(Scheme 4, eqn (2)) and the control experiment without gold
was also performed, whose results verified the significance of
Scheme 4 Control experiments using indene intermediate 2.
the catalyst in the oxidation step, which was consistent with
the first attempt at the very beginning (Scheme 4, eqn (3)).
To confirm that indene 2 was the true intermediate of the
oxidation, the reaction kinetic profiles under various con-
ditions were performed as shown in Scheme 5. A very faster
rate from substrate 1 to indene 2 was observed, which indi-
cated that indene 2 could be generated easily under the reac-
tion conditions. In the transformation from substrate 1 to
indenone 3, it was found that the yield of product 3 would
increase gradually accompanied by the slow consumption of
indene 2. And the similar kinetic profiles observed from the
oxidations of 1 to 3 and 2 to 3 strongly supported that indene
2 should be the active intermediate in the oxidation process.
According to the precedent study, a radical mechanism may
be involved in this transformation.8–10 The verification experi-
ments using the radical inhibitor butylated hydroxytoluene
(BHT) are summarized in Scheme 6. The formation of inde-
none 3 from indene 2 was completely blocked in the presence
of 1 equivalent amount of BHT. However, the treatment of
intermediate 2 with the combination of a gold catalyst and the
radical initiator azodiisobutyronitrile (AIBN) gave a messy reac-
Scheme 3 Control experiments under an 18O2 atmosphere.
Scheme 5 Reaction kinetic profiles under various conditions.
Org. Biomol. Chem., 2018, 16, 9147–9151 | 9149
This journal is © The Royal Society of Chemistry 2018

View Article Online
Communication
Organic & Biomolecular Chemistry
Scheme 6 Radical verification experiments.
Scheme 8 The formal total synthesis of isoprekinamycin.
tion profile. It indicated that the gold catalyst and radical con-
ditions were incompatible, which had been described in the
precedent literature.8 Then a following experiment by treating
the substrate 2 with AIBN itself and O2 led to the generation of
the desired product 3 in a much shorter time. These results
suggested that the oxidation by O2 might happen via some
radical intermediates.13
Based on the experimental results, a plausible mechanism
was proposed as depicted in Scheme 7. Activation of the
alkyne in 1i promoted a 5-endo-dig cyclization of enol ether to
produce the indene 2i after protodeauration. A following
radical addition of 18O2 to intermediate 2i resulted in the for-
mation of 2i-1, which underwent an isomerization to give 2i-2.
Coordination of cationic Au species with the oxygen atom
initiated the cleavage of the 18O–18O bond to provide the
oxonium intermediate 2i-3, which could be captured by H218O
or H2O to generate the indenone 3i-1 or 3i-2 after removing the
methoxyl group.
Significantly, the assembly of highly functionalized inde-
nones with this unique method allowed the rapid preparation
of structurally diverse molecules by functional group manipu-
lations. In order to expand the utility of this method further,
isoprekinamycin, a cytotoxic benzo[a]fluorene natural product
was chosen as our target. Retrosynthetically, isoprekinamycin
could be disconnected into indenone intermediate 5, which
was the key intermediate in Dmitrienko’s total synthesis of
this molecule.14 Our synthesis started from gold(I)-catalyzed
tandem cyclization reaction of 1s to give indenone 3s in 61%
yield under the optimal conditions. The transformation from
3s to ester 5 by Pinnick oxidation and esterification achieved
the formal total synthesis of isoprekinamycin by providing the
Dmitrienko’s key intermediate (Scheme 8).
In summary, we have developed a unique strategy for the
synthesis of indenones by a gold(I)-catalyzed cyclization/
aerobic oxidation cascade reaction from simple aryl 1,5-enyne
substrates. The possible mechanism was probed based on
heavy isotope labelling and a series of control experiments.
The application of this method to the formal total synthesis of
isoprekinamycin was achieved. Notably, molecular oxygen, the
most environmentally friendly oxidant, was employed com-
bined with a gold catalyst to provide indenone scaffolds in a
single step from acyclic precursors.
Conflicts of interest
Scheme 7 The proposed mechanism.
There are no conflicts to declare.
9150 | Org. Biomol. Chem., 2018, 16, 9147–9151
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Communication
S. A. Kozmin, J. Am. Chem. Soc., 2004, 126, 11806;
(e) F. Gagosz, Org. Lett., 2005, 7, 4129; (f) L. M. Zhang and
S. A. Kozmin, J. Am. Chem. Soc., 2005, 127, 6962;
(g) S. Wang and L. Zhang, J. Am. Chem. Soc., 2006, 128,
14274; (h) A. S. K. Hashmi, Pure Appl. Chem., 2010, 82,
1517; (i) J. Sun, M. P. Conley, L. Zhang and S. A. Kozmin,
J. Am. Chem. Soc., 2006, 128, 9705; ( j) D. Vasu, H. H. Hung,
S. Bhunia, S. A. Gawade, A. Das and R. S. Liu, Angew.
Chem., Int. Ed., 2011, 50, 6911.
Acknowledgements
Financial support for this research was provided by the
Natural Science Foundation of Liaoning Province of China
(Grants 20170540855) and the Liaoning Province Education
Administration of China (Grants 2017LQN08 & LR2017043).
We thanked the program for innovative research team of the
Ministry of Education and program for Liaoning innovative
research team in university.
6 D. Vasu, H. H. Hung, S. Bhunia, S. A. Gawade, A. Das and
R. S. Liu, Angew. Chem., Int. Ed., 2011, 50, 6911.
7 For selected examples of aerobic oxidation of sp2 C–H
bonds, see: (a) R. Neumann and M. Dahan, Nature, 1997,
388, 353; (b) Y. Ishii, S. Sakaguchi and T. Iwahama, Adv.
Synth. Catal., 2001, 343, 393; (c) A. S. K. Hashmi,
M. C. Blanco Jaimes, A. M. Schuster and F. Rominger,
J. Org. Chem., 2012, 77, 6394; (d) L. Wang, Y. Zhu, J. Wang,
F. Liu, J. Huang, X. Meng, J. M. Basset, Y. Han and
F. S. Xiao, Nat. Commun., 2015, 6, 6957; (e) A. Gonzalez-de-
Castro and J. Xiao, J. Am. Chem. Soc., 2015, 137, 8206;
(f) X. Sun, X. Li, S. Song, Y. Zhu, Y. Liang and N. Jiao, J. Am.
Chem. Soc., 2015, 137, 6059; (g) A. A. Andia, M. R. Miner
and K. A. Woerpel, Org. Lett., 2015, 17, 2704.
Notes and references
1 (a) B. A. Brooks, A. F. Lant, W. R. McNabb and
F. H. Noormohamed, Br. J. Clin. Pharmacol., 1984, 17, 497;
(b) R. S. Laufer and G. I. Dmitrienko, J. Am. Chem. Soc.,
2002, 124, 1854; (c) B. L. Staker, M. D. Feese, M. Cushman,
Y. Pommier, D. Zembower, L. Stewart and A. B. Burgin,
J. Med. Chem., 2005, 48, 2336; (d) R. S. Senaiar, J. A. Teske,
D. D. Young and A. Deiters, J. Org. Chem., 2007, 72, 7801;
(e) Z. Luo, J. Sheng, Y. Sun, C. Lu, J. Yan, A. Liu, H. Luo,
L. Huang and X. Li, J. Med. Chem., 2013, 56, 9089;
(f) D. J. Kerr, M. Miletic, N. Manchala, J. M. White and
B. L. Flynn, Org. Lett., 2013, 15, 4118.
8 H. Peng, N. G. Akhmedov, Y. Liang, N. Jiao and X. Shi,
J. Am. Chem. Soc., 2015, 137, 8912.
9 A. S. K. Hashmi, M. C. Blanco Jaimes, A. M. Schuster and
F. Rominger, J. Org. Chem., 2012, 77, 6394.
2 (a) J. P. Scott, M. S. Ashwood, K. M. J. Brands, S. E. Brewer,
C. J. Cowden, U. Dolling, K. M. Emerson, A. D. Gibb,
A. Goodyear, S. F. Oliver, G. W. Stewart and D. J. Wallace,
Org. Process Res. Dev., 2008, 12, 723; (b) J. T. Mohr, 10 D. V. Patil, H. S. Park, J. Koo, J. W. Han and S. Shin, Chem.
M. R. Krout and B. M. Stoltz, Nature, 2008, 455, 323.
Commun., 2014, 50, 12722.
3 (a) T. Miura and M. Murakami, Org. Lett., 2005, 7, 3339; 11 (a) Y. Liu, J. Guo, Y. Liu, X. Wang, Y. Wang, X. Jia, G. Wei,
(b) P. A. Wender, T. J. Paxton and T. J. Williams, J. Am.
Chem. Soc., 2006, 128, 14814; (c) H. Tsukamoto and
Y. Kondo, Org. Lett., 2007, 9, 4227; (d) Y. Harada,
J. Nakanishi, H. Fujihara, M. Tobisu, Y. Fukumoto and
N. Chatani, J. Am. Chem. Soc., 2007, 129, 5766; (e) Z. Qi,
M. Wang and X. Li, Org. Lett., 2013, 15, 5440; (f) J. Zhang,
L. Chen, J. Xiao and M. Cheng, Chem. Commun., 2014, 50,
6243; (b) X. Peng, L. Zhu, Y. Hou, Y. Pang, Y. Li, J. Fu,
L. Yang, B. Lin, Y. Liu and M. Cheng, Org. Lett., 2017, 19,
3402; (c) Z. Xiong, X. Zhang, Y. Li, X. Peng, J. Fu, J. Guo,
F. Xie, C. Jiang, B. Lin, Y. Liu and M. Cheng, Org. Biomol.
Chem., 2018, 16, 7361.
D. Wu, X. Chen, Y. Liu and Z. Xu, J. Org. Chem., 2014, 79, 12 (a) C. Zhang and N. Jiao, J. Am. Chem. Soc., 2010, 132, 28;
4799.
(b) T. Wang and N. Jiao, J. Am. Chem. Soc., 2013, 135,
4 P. Nösel, L. N. dos Santos Comprido, T. Lauterbach,
11692.
M. Rudolph, F. Rominger and A. S. K. Hashmi, J. Am. 13 (a) A. Laguna and M. Laguna, Coord. Chem. Rev., 1999, 193,
Chem. Soc., 2013, 135, 15662.
5 (a) A. S. K. Hashmi, T. M. Frost and J. W. Bats, J. Am. Chem.
Soc., 2000, 122, 11553; (b) V. Mamane, T. Gress, H. Krause
837; (b) B. Sahoo, M. N. Hopkinson and F. Glorius, J. Am.
Chem. Soc., 2013, 135, 5505; (c) X. Shu, M. Zhang, Y. He,
H. Frei and F. D. Toste, J. Am. Chem. Soc., 2014, 136, 5844.
and A. Furstner, J. Am. Chem. Soc., 2004, 126, 8654; 14 W. Liu, M. Buck, N. Chen, M. Shang, N. J. Taylor, J. Asoud,
(c) M. R. Luzung, J. P. Markham and F. D. Toste, J. Am.
Chem. Soc., 2004, 126, 10858; (d) L. M. Zhang and
X. Wu, B. B. Hasinoff and G. I. Dmitrienko, Org. Lett., 2007,
9, 2915.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 9147–9151 | 9151