Gold-Catalyzed Oxidation/C?H Functionalization of Ynones: Efficient and Rapid Access to Functionalized Polycyclic Salicyl Ketones

Article abstract of DOI:10.1002/chem.201600736

An efficient strategy to construct salicyl ketones through gold-catalyzed oxidation/C?H functionalization of ynones is reported. A variety of functionalized salicyl ketones are readily accessed by utilizing this non-diazo approach, thus providing a viable

Full text of DOI:10.1002/chem.201600736

DOI: 10.1002/chem.201600736
Full Paper
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Synthetic Methods
Gold-Catalyzed Oxidation/CÀH Functionalization of Ynones:
Efficient and Rapid Access to Functionalized Polycyclic Salicyl
Ketones
Kegong Ji,* Fang Yang, Shiyue Gao, Jiangjiang Tang, and Jinming Gao[a]
Abstract: An efficient strategy to construct salicyl ketones
through gold-catalyzed oxidation/CÀH functionalization of
ynones is reported. A variety of functionalized salicyl ketones
are readily accessed by utilizing this non-diazo approach,
thus providing a viable alternative to synthetically useful sal-
icyl ketones with a yield up to 98%. The a-oxo gold car-
benes generated in situ through gold-catalyzed oxidation of
ynones can be trapped effectively by internal aryl and heter-
oaromatic groups. Electronic and steric effects were also in-
vestigated in this reaction. The anticancer activity of one sal-
icyl ketone analogue was investigated and its cytotoxicity
assays against the PC-3 prostate cancer cell line and SKOV-3
human ovarian carcinoma cell line yield IC50 were 0.81Æ0.05
and 0.87Æ0.15 mm, respectively, demonstrating that salicyl
ketone analogues showed good anticancer activity.
Introduction
and represents a promising alternative to the generation of a-
oxo metal carbenes from the hazardous and potentially explo-
sive a-diazo ketone precursors.[3–11] Ynones are electron-defi-
cient alkynes in which the CꢀC triple bond is polarized sub-
stantially by the carbonyl group, which causes the distal end
of the ynone to be significantly more electron-deficient than
the proximal end, thereby inviting preferential attack by ap-
proaching nucleophiles (Scheme 1, Eq. (1)).[6,12,13] The strategy
of gold-catalyzed oxidation of ynones has also been developed
with the generated a-oxo gold carbene intermediates trapped
in situ by relatively electron-rich nucleophiles, such
The salicyl group is an important motif in natural products and
biologically active molecules (Figure 1).[1] Salicyl analogues as
pharmocologically interesting compounds are also potentially
useful precursors for a variety of functional group transforma-
tions and drug discovery programs. In this context, the devel-
opment of efficient methods to synthesis functionalized aro-
matic salicyl derivatives with selective control of substitution
patterns continues to be actively pursued.
as oxygen and C=C double bonds.[12] Recently,
Zhang and co-workers reported gold(I)-catalyzed in-
tramolecular oxidation-cyclopropanation of 1,6-
enynes to [n.1.0]bicycloalkanes with the C=C double
bonds trapping the a-oxo gold carbene intermedi-
ates (Scheme 1, Eq. (2)).[6a,c] Later, Yang and co-work-
ers reported the gold-catalyzed oxidation of ynones
to dihydrofuran-3-ones with the oxygen atom trap-
Figure 1. Biologically active molecules containing the salicyl group
ping the a-oxo gold carbene intermediates using
1.1 equiv of Yb(OTf)3 as co-catalyst (Scheme 1,
Eq. (3)).[12a] In contrast, the use of an unactivated aryl
Recently, gold-catalyzed alkyne oxidations using pyridine/
quinoline N-oxides as oxidants for the generation of a-oxo
gold-carbene/carbenoid intermediates to synthesize various
useful molecules were reported.[2] This strategy is safe, green,
sp2 carbon as a nucleophile to trap the a-oxo gold carbene in-
termediates efficiently proved to be challenging because of
the double oxidation of ynones and other intractable side reac-
tions.[12c] Thus, reports on the successful use of unactivated aryl
sp2 carbon to trap the a-oxo gold carbene generated in situ
from ynones are limited. To further develop ynones as surro-
gates of hazardous a-diazo ketones in gold catalysis, we fo-
cused here on expanding the scope of suitable internal nucleo-
philes such as aryl groups. Our first target was o-aryl ynones
(Scheme 1, Eq. (4)). Notably, the reaction would offer efficient
and rapid access to functionalized polycyclic salicyl ketone ana-
logues under mild conditions.
[a] Prof. Dr. K. Ji, Dr. F. Yang, S. Gao, Dr. J. Tang, Prof. Dr. J. Gao
Shaanxi Key Laboratory of Natural Products & Chemical Biology
College of Science, Northwest A&F University
3 Taicheng Road, Yangling 712100, Shaanxi (P.R. China)
E-mail: jikegong@nwsuaf.edu.cn
Supporting Information (1H, 13C NMR, IR, and HRMS data
for new compounds) for this article can be found under
http://dx.doi.org/10.1002/chem.201600736.
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with aromatic R groups. Various electron-donating
and electron-withdrawing R groups were tolerated
(1b–d). Steric effects of the R aryl groups was also
considered. By installing a methyl or bromide group
in the ortho position (1e vs. 1 f) it was found that
the substrate with the o-methyl aryl group gave
better yield than that with an o-bromide aryl group.
O-Phenyl ynone 1h, with a heteroaromatic R group,
afforded the desired product 3h in 91% yield. Fur-
thermore, substrates such as 1i–j, with an aliphatic
R group, also gave the desired product 3i–j in good
yield. Other ynones such as 1k–o, with different R’
group, were also investigated. Substrates such as
1k, with the methyl R’ group at the meta-position,
showed excellent selectivity, giving the correspond-
ing product 3k in 92% yield by selective CÀH func-
tionalization of the para-sp2 carbon of the methyl on
the phenyl moiety. The relative configuration of the
product 3k was unambiguously assigned by X-ray
crystallographic analysis (Figure 2).[14] Other ynones
such as 1l–m, with an electron-donating or electron-
withdrawing R’ group on the para-position, also
gave the desired product 3l–m in acceptable yield.
Interestingly, instead of o-phenyl ynones, ynones
Scheme 1. Design of the reaction from ynones.
Results and Discussion
At the outset, we used o-phenyl ynone 1a and pyridine 1-
oxide as the oxidant; the results of optimization studies are
shown in Table 1. Initially, we used 0.15 mmol 1a and N-oxide
2a (1.5 equiv) with Ph3PAuNTf2 (5 mol%) as catalyst; to our de-
light, the desired product (10-hydroxyphenanthren-9-yl)(phe-
nyl)methanone (3a) was obtained in 98% isolated yield after
3 h in fluorobenzene (PhF) at room temperature, and no 7-
phenyl-5H-dibenzo[a,c][7]annulen-5-one (4) was observed
(entry 1). An alternative N-oxide, 2,6-dichloropyridine N-oxide
(2b), was also investigated and this provided a similar result
(entry 2). N-Oxides 2c–e were also tested, but the results were
not improved even after longer reaction time (entries 3–5).
Other cationic gold complexes derived from typical ligands
such as X-Phos, IPr were less effective (entries 6 and 7). The
use of Mor-DalPhosAuNTf2 (5 mol%) also promoted the reac-
tion and gave an excellent yield (entry 8). Gold(III) complexes
such as AuCl3 were largely ineffective, resulting in ynone 1a re-
maining with little desired product. Other catalysts such as
AgNTf2, Zn(OTf)2, Hg(OTf)2, and PtCl2 were also investigated,
but were ineffective. Solvent effects were considered through
the use of tetrahydrofuran (THF), 1,2-dichloroethane (DCE), and
toluene, but no effective solvent was found. Upon decreasing
the gold catalyst loading to 2 mol%, an acceptable result (74%
yield) was observed after 7 h. No reaction occurred in the ab-
sence of Ph3PAuNTf2.
Table 1. Screening conditions.[a]
Entry
N-Oxide [equiv]
Catalyst [mol%]
Yield [%][b]
1
2
3
4
5
6
7
8
2a (1.5)
2b (1.5)
2c (1.5)
2d (1.5)
2e (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
Ph3PAuNTf2 (5)
Ph3PAuNTf2 (5)
Ph3PAuNTf2 (5)
Ph3PAuNTf2 (5)
Ph3PAuNTf2 (5)
XPhosAuCl (5) +AgNTf2 (5)
IPrAuCl (5) +AgNTf2 (5)
Mor-DelPhosAuNTf2 (5)
AuCl3 (5)
98
97
68
70
NR
81
62
92
<10[c]
NR
71[d]
79[e]
64[f]
74[g]
NR
9
10
11
12
13
14
15
16
17
18
AgNTf2 (5)
Ph3PAuNTf2 (5)
Ph3PAuNTf2 (5)
Ph3PAuNTf2 (5)
Ph3PAuNTf2 (2)
–
Zn(OTf)2 (5)
Hg(OTf)2 (5)
PtCl2 (5)
With the optimized reaction conditions established (Table 1,
entry 1), the scope of the transformation was examined with
various o-phenyl ynones, as shown in Table 2. Thus, a tandem
gold-catalyzed oxidation/CÀH functionalization of ynones 1a–
s proceeded smoothly to provide the corresponding products
3a–s in moderate to excellent yield. The reaction worked well
NR
trace
NR
[a] Reaction was run with everything in a vial capped with a septum; ini-
tially, [1a]=0.1m. [b] Isolated yield. [c] 30% Conversion based on SM.
[d] Solvent DCE. [e] Solvent toluene. [f] Solvent THF. [g] Reaction time 7 h.
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acceptable yield. Ynones such as 1p–q, with different R’’
group were also studied and the substrates with different elec-
tron-donating and electron-withdrawing R’’ groups proceeded
smoothly to provide the corresponding products 3p–q in
moderate to excellent yield. Considering other synthetically
useful transformations, ynones such as 1r–s, with different ali-
phatic groups, were also tested and the reaction worked well
to afford 3r–s in good yield.
Table 2. Scope of polycyclic salicyl ketones 3.[a]
To gather additional experimental evidence for the mecha-
nism, we examined the direct conversion of ynone 5 by instal-
ling an alkene group on the ortho-position in the presence of
5 mol% of Mor-DalPhosAuNTf2. To our delight, this reaction
worked well and afforded 6a-benzoyl-1-phenyl-1a,6a-dihydro-
cyclopropa[a]inden-6(1H)-one (6) in 95% yield with the C=C
double bond trapping the a-oxo gold carbene intermediate
(Eq. (5)).
On the basis of the above observations, we propose the fol-
lowing plausible mechanisms for this transformation (Figure 3).
1) Coordination of the ynone moiety with the cationic gold
complex and attack of the N-oxide on the distal end of the
ynone gives complex A. 2) Gold complex back donation of an
electron removes the pyridine to give the a-oxo gold carbene
intermediate B, followed by internal aryl sp2 carbon trapping
to afford intermediate C. 3) Intermediate C releases the cationic
gold complex to afford product 3 through aryl isomerization.
The anticancer activity of salicyl ketone analogue 3c was in-
vestigated and its cytotoxicity assays against the PC-3 prostate
cancer cell line and SKOV-3 human ovarian carcinoma cell line
[a] Initially, [1]=0.1m. The reactions were run under the standard condi-
tions, unless otherwise specified. [b] Yields of isolated products are
shown.
Figure 2. X-ray structure of 3k.[14]
1n–o, with a heteroaromatic group such as thiophene andben-
zo[b]thiophene on the ortho-position, were also CÀH function-
alized selectively to afford the corresponding products 3n–o in
Figure 3. Proposed mechanism.
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The residue was purified by chromatography on silica gel (hex-
anes/ethyl acetate) to afford the desired (10-hydroxyphenanthren-
9-yl)(phenyl)methanone 3a–s.
(10-Hydroxyphenanthren-9-yl)(phenyl)methanone (3a): 1H NMR
(500 MHz, CDCl3): d=12.75 (s, 1H), 8.60 (dd, J=11.2, 4.3 Hz, 2H),
8.53 (d, J=8.2 Hz, 1H), 7.86–7.76 (m, 1H), 7.69 (dd, J=11.6, 4.5 Hz,
1H), 7.66–7.61 (m, 2H), 7.56–7.51 (m, 1H), 7.42–7.33 (m, 4H),
7.18 ppm (qd, J=7.0, 3.5 Hz, 1H); 13C NMR (126 MHz, CDCl3): d=
200.19, 160.64, 140.34, 133.99, 132.41, 130.59, 130.25, 129.42,
128.45, 127.65, 127.08, 126.13, 125.89, 125.21, 125.05, 124.40,
122.83, 122.59, 110.97 ppm; IR (neat): n˜ =1617, 1447, 1305, 1010,
753, 722 cmÀ1; HRMS: m/z calcd for C21H15O2+: 299.1067 [M+H+];
found: 299.1069.
General procedure B: Gold-catalyzed oxidation/cyclopropanation
of ynone 5 to 6a-benzoyl-1-phenyl-1a, 6a-dihydrocyclopropa[a]in-
den-6(1H)-one (6). To a 3 dram vial containing 3 mL of PhF were
added sequentially the ynone 5 (0.15 mmol), 8-methylqunoline N-
oxide N-oxide 2a (29 mg, 0.225 mmol, 1.2 equiv), and Mor-DalPho-
sAuNTf2 (6.9 mg, 0.003 mmol). The resulting mixture was stirred at
258C and the progress of the reaction was monitored by TLC.
Upon completion, the reaction mixture was concentrated under
vacuum. The residue was purified by chromatography on silica gel
(hexanes/ethyl acetate) to afford the desired 6a-benzoyl-1-phenyl-
1a, 6a-dihydrocyclopropa[a]inden-6(1H)-one (6).
Figure 4. Salicyl ketone analogue 3c reduces the proliferation of cancer
cells. The IC50 values represent the concentration resulting in 50% inhibition
of cell proliferation. Cells were grown and treated with 3c at 0–2 mm, PC-3
cells for 48 h, and SKOV-3 cells for 72 h. All data (mean ÆSD) are the aver-
age of three determinations.
indicated IC50 values of 0.81Æ0.05 and 0.87Æ0.15 mm, respec-
tively, demonstrating that the salicyl ketone analogues exhibit
good anticancer activity (Figure 4).
6a-Benzoyl-1-phenyl-1a,6a-dihydrocyclopropa[a]inden-6(1H)-one
(6): 1H NMR (500 MHz, CDCl3): d=7.92–7.86 (m, 2H), 7.75 (d, J=
7.6 Hz, 1H), 7.61–7.55 (m, 2H), 7.49–7.44 (m, 1H), 7.41–7.33 (m,
3H), 7.17–7.09 (m, 5H), 4.13 (d, J=4.3 Hz, 1H), 3.24 ppm (d, J=
4.4 Hz, 1H); 13C NMR (126 MHz, CDCl3): d=195.36, 191.42, 151.67,
136.72, 134.43, 134.08, 133.98, 133.37, 130.25, 128.36, 127.94,
127.81, 127.71, 127.36, 125.62, 125.01, 57.17, 53.83, 30.73 ppm. IR
(neat): n˜ =1711, 1658, 1347, 1009, 752, 684 cmÀ1; HRMS: m/z calcd
for C23H17O2+: 325.1223 [M+H+]; found: 325.1225.
Conclusion
We have described an efficient strategy to construct salicyl ke-
tones through gold-catalyzed oxidation/CÀH functionalization
of ynones. A variety of functionalized salicyl ketones are readily
accessed by utilizing this non-diazo approach, thus providing
a viable alternative route to synthetically useful salicyl ketones.
The anticancer activity of salicyl ketone analogue 3c against
the PC-3 and prostate cancer cell line and SKOV-3 human ovar-
ian carcinoma cell line was also investigated and showed good
biological activity.
Acknowledgements
We are grateful for the financial support from National Natural
Science Foundation of China (NSF-21502150) and Youth Train-
ing Programme and Northwest A&F University (Z111021404).
Experimental Section
General experimental details: Column chromatography was car-
ried out on silica gel. Unless noted, H NMR spectra were recorded
1
Keywords: antitumor agents · carbenes · CÀH activation ·
gold · oxidation
at 500 MHz in CDCl3 and 13C NMR spectra were recorded at
125 MHz in CDCl3 with trimethylsilane (TMS) as internal standard.
IR spectra were recorded with a FTIR spectrometer, and only the
major peaks are reported (in cmÀ1). Melting points were deter-
mined with a microscopic apparatus and are uncorrected. All new
compounds were further characterized by elemental analysis or
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General procedure A: Gold-catalyzed oxidation/CÀH functionaliza-
tion of ynones to functionalized polycyclic salicyl ketones 3. To
a 3 dram vial containing 3 mL of PhF were added sequentially
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Received: February 17, 2016
[8] For selected examples: a) C.-W. Li, G. Y. Lin, R. S. Liu, Chem. Eur. J. 2010,
16, 5803–5811; b) C.-W. Li, K. Pati, G.-Y. Lin, S. M. A. Sohel, H.-H. Hung,
Published online on && &&, 0000
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
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Synthetic Methods
K. Ji,* F. Yang, S. Gao, J. Tang, J. Gao
&& – &&
Gold-Catalyzed Oxidation/CÀH
Functionalization of Ynones: Efficient
and Rapid Access to Functionalized
Polycyclic Salicyl Ketones
A golden route: An efficient strategy to
construct salicyl ketones through gold-
catalyzed oxidation/CÀH functionaliza-
tion of ynones is reported (see scheme).
A variety of functionalized salicyl ke-
tones are readily accessed by utilizing
this non-diazo approach, thus providing
a viable alternative to synthetically
useful salicyl ketones.
&
&
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!