Gold(I)-Catalyzed Domino Cyclization for the Synthesis of Tricyclic Chromones

Article abstract of DOI:10.1055/s-0034-1380715

A simple and efficient method for the synthesis of tricyclic chromones has been developed. In this approach, tricyclic chromones were synthesized from a diverse range of phenols and alkynes through a Sonogashira coupling and subsequent gold-catalyzed intr

Full text of DOI:10.1055/s-0034-1380715

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Georg Thieme Verlag Stuttgart · New York
2015, 26, 1461–1464
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letter
Synlett
Z. Li et al.
Letter
Gold(I)-Catalyzed Domino Cyclization for the Synthesis of Tricyclic
Chromones
Zhiqiang Lia,b
Qingjiang Lic,d
Guo-Kai Liub,e
AcO R2
O
R2
OH
n
[Au]-catalyzed
domino cyclization
R1
Weimin Chen*a
Xiao-Shui Pengb,c
Henry N. C. Wong*b,c
MeO
MeO
n
O
R1
9 examples, 62–83%
n = 1, 2
a
College of Pharmacy, Jinan University, Guangzhou, P. R. of China
twmchen@jnu.edu.cn
Shenzhen Municipal Key Laboratory of Chemical Synthesis of Medicinal Organic Molecules &
1
R
R
= H, Me, F
= H, Me
2
b
Shenzhen Center of Novel Functional Molecules, Shenzhen Research Institute,
The Chinese University of Hong Kong, No.10, 2nd Yuexing Road, Shenzhen 518507,
P. R. of China
c
Department of Chemistry, Centre of Novel Functional Molecules and State Key Laboratory
of Synthetic Chemistry, The Chinese University of Hong Kong, Shatin, New Territories,
Hong Kong SAR, P. R. of China
hncwong@cuhk.edu.hk
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006,
d
P. R. of China
e
Department of Pharmacy, School of Medicine, Shenzhen University,
No.3688, Nanhai Road, Nanshan, Shenzhen 518060, P. R. of China
Received: 07.03.2015
Accepted after revision: 14.04.2015
Published online: 03.06.2015
chromones was possible from ω-formyl-α,β-unsaturated
carbonyl compounds through a Baylis–Hillman reaction
(Scheme 1).11
DOI: 10.1055/s-0034-1380715; Art ID: st-2015-b0160-l
Abstract A simple and efficient method for the synthesis of tricyclic
chromones has been developed. In this approach, tricyclic chromones
were synthesized from a diverse range of phenols and alkynes through
a Sonogashira coupling and subsequent gold-catalyzed intramolecular
domino cyclization.
O
O
XR
OH
Pb(OAc)4
HO
n
RX
Baylis–Hillman
reaction
R = MOM, H
X = O, S
Key words chromone, gold-catalyzed, intramolecular cyclization,
domino, Brønsted acid
n
O
O
HO
The synthesis of heterocycles plays an important role in
the design and identification of new physiological/pharma-
cologically active compounds. The chromone ring system,
H+
n
X
n
RX
1
-benzopyran-4-one, is the core fragment in several flavo-
Scheme 1 Synthesis of tricyclic chromones through Baylis–Hillman re-
action
1,2
noids, such as flavones, flavonols and isoflavones. The
rigid chromone motif has been classified as a privileged
structure in drug discovery due to its use in a wide variety
of pharmacologically active compounds with antibacterial,
anticancer, anti-HIV, anti-oxidant, and anti-inflammato-
ry properties. Chromone derivatives are also photoactive
and can be used easily in a range of photoinduced reactions,
affording diverse heterocyclic compounds. The main objec-
Therefore, we initiated a program to synthesize a series
of tricyclic chromone derivatives by using mild reaction
conditions. Herein, we report our preliminary results on
the synthesis of substituted tricyclic chromones from 2-io-
dophenols 3 and terminal alkynes 4 (Scheme 2) through a
Sonogashira coupling and a gold(I)-catalyzed intramolecu-
3
4
5
6
7
8
tives of chromone syntheses are not only the development
of more diverse and complex bioactive compounds for
structure–activity relationship (SAR) evaluations, but also
other applications in medicinal chemistry, such as the
preparation of fluorescence probes, due to the photochemi-
lar domino cyclization. AuCl(PPh ) was chosen as the cata-
3
lyst because simple AuCl or AuCl , especially cationic com-
3
plexes generated by chloride abstraction from [AuCl(PPh )]
3
or similar phosphine complexes {employing one equivalent
of a silver salt with a non-coordinating anion to generate
9
cal properties of chromones. Over the years, a number of
the corresponding cationic species [Au(S)(PPh )]X (S = sol-
3
chromone derivatives have been synthesized,1 but only
0
vent or substrate molecule)}, are sufficiently alkynophilic
12
Koo and co-workers reported that the synthesis of tricyclic
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Z. Li et al.
Letter
to catalyze many reactions of the more reactive enynes13
and they are particularly suitable for an intramolecular cy-
clization.
Table 1 Reaction Optimization
14
AcO
OH
O
O
AuCl(PPh3) (10 mol%)
R2
AgX
R2 OH
OAc
MeO
MeO
OH
R1
OTBS
solvent, r.t.
i. Ac2O
1b
2b
n
n
MeO
MeO
MeO
MeO
ii. NH2NH2
b
Entry
AgX (equiv)
–
Time (h)
Solvent
Yield (%)
R1
5
1
1
2
3
4
0.5
0.5
5
CH
CH
CH
2
2
2
Cl
Cl
Cl
2
2
NR
33
25
37
71
70
n = 1, 2
AuCl(PPh3)
AgOTf
then p-TsOH•H2O
AgSbF
AgNTf
AgSbF
6
2
6
(0.1)
(0.1)
(0.1)
1
R
R
= H, Me, or F
= H, Me
Sonogashira
2
2
0.5
0.25
0.5
ClCH
2
CH
2
Cl
Cl
5a
AgOTf (0.1)
AgSbF (0.1)
CH Cl
OTBS
O
R2
2
2
R2 OH
I
R1
6b
6
ClCH
2
CH
2
OMe
OMe
+
a
n
p-TsOH·H O (1 equiv) was added after 15 min, then the mixture was heat-
2
O
n
ed to reflux for 6 h.
b
R1
2
p-TsOH·H O (1.5 equiv) was added after 30 min, then the mixture was
heated to reflux for 1.5 h.
3
4
2
Scheme 2 Synthesis of tricyclic chromones through gold-catalyzed
domino cyclization
ble 2, the relevant transformation was found to be very typ-
ical and applicable. Some of the resulting tricyclic
chromones could be applied to natural product and drug
syntheses, and even in materials science. Under the afore-
mentioned optimized conditions, a range of starting mate-
rials 1a–i, prepared from 2-iodophenol moieties 3a–c and
terminal alkynes 4a–c, underwent the domino cyclization
To introduce different substituents on cyclization pre-
cursors 1, alcohols 5a–i were prepared, mainly through a
15
classical Sonogashira coupling reaction between 3 and 4,
with acceptable yields. Upon sequential desilylation and
acetylation of alcohols 5a–i, alkynes 1a–i were obtained in
almost quantitative yields. We then turned our attention to
the optimization of the cyclization conditions towards the
synthesis of tricyclic chromones. As shown in Table 1, 1-(2-
hydroxyphenyl)-6,6-dimethoxyhex-1-yn-3-yl acetate (1b)
was employed as a model substrate. After extensive investi-
gations, we found that this domino cyclization was only
promoted by a gold-catalyzed [3,3]-sigmatropic acetate re-
arrangement to form the corresponding allenyl acetate,16
which could promote this tandem reaction. Moreover, to in-
vestigate a possible counterion effect, among the anion
sources available, the readily available silver salts (AgOTf,
AgNTf , AgSbF ) were screened to assess their influence on
17
to give the corresponding chromone derivatives 2a–i. The
presence of electron-withdrawing groups in substrates
(1g–i and 2-iodophenol 3c) slowed down the reaction, but
the relevant products were still obtained in moderate yields
(51–56%).
A plausible mechanism18 for the annulation of 1b cata-
lyzed by gold(I) in the presence of p-TsOH·H O is proposed
2
in Scheme 3. Intermediate allene A can be formed through
gold-catalyzed 1,3-acetate migration of 1b. Thus, upon sub-
sequent gold-catalyzed elimination of methoxyl and intra-
molecular nucleophilic addition via B, C can then be
formed. Presumably, either Brønsted acid p-TsOH·H O or
2
6
2
the domino cyclization. Thereafter, a variety of reaction
conditions (silver salt, temperature) were examined; repre-
sentative results are shown in Table 1. It was found that Ag-
OTf was the best counterion silver source for this reaction
among the silver salts tested. Moreover, the highest yield
for the reaction (71%; entry 5) was obtained when a mix-
Lewis acid gold(I) could activate the final ether formation
through cleavage of the methoxyl group to provide tricyclic
chromone 2b.
In summary, we have developed a simple and efficient
Au-catalyzed domino protocol for the synthesis of a diverse
range of tricyclic chromones from 2-iodophenol 3 and ter-
minal alkynes 4 in good isolated yields under mild condi-
tions. Given the ready availability of the starting materials
and the potential applications of the chromone products,
this protocol should be useful in organic synthesis and me-
dicinal chemistry. Further studies on the synthetic applica-
tions of this reaction are in progress in our laboratory.
ture of 1b, AuCl(PPh ) (0.1 equiv), and AgOTf (0.1 equiv) in
3
CH Cl was stirred for 15 minutes, then p-TsOH·H O (1.0
2
2
2
equiv) was added and the mixture was heated at reflux for
hours.
With the optimized conditions in hand, we then investi-
6
gated the substrate scope of the gold-catalyzed domino cy-
clization towards tricyclic chromones. As illustrated in Ta-
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Z. Li et al.
Letter
Table 2 Synthesis of Tricyclic Chromones Catalyzed by Gold(I)
R2 OH
OTBS
O
R2
Sonogashira
coupling
optimized
conditions
R1
OMe
OMe
+
i. Ac2O
2
n
5
1
R1
I
ii. NH NH
2
O
2
n
1
2
3
3
3
a: R = H
b: R = Me
c: R = F
4a: n = 1, R = H
1
2
4b: n = 1, R = Me
1
2
4c: n = 2, R = H
Entry
1
3a
4
Yield of 1 (%)b,c
1a (66)
Yield of 2 (%)
O
OTBS
I
4a
4b
4c
4a
4b
4c
4a
4b
4c
O
3
a
2a (66)
2b (71)
2c (70)
2d (65)
2e (71)
2f (72)
O
2
3
4
5
6
7
8
3a
3a
1b (68)
1c (71)
1d (62)
1e (77)
1f (72)
1g (82)
1h (83)
1i (79)
O
O
O
O
I
TBSO
O
O
3
b
3b
3b
O
O
O
O
I
F
TBSO
F
O
O
3
c
2
g (56)
F
3c
3c
O
O
2
h (51)
F
9
O
2
i (54)
(0.04 mmol), CuI (0.04 mmol), DIPEA (3.2 mmol), THF (2 mL), 55 °C, 5 h.
) (0.02 mmol), AgOTf (0.02 mmol), 15 min; ii. p-TsOH·H O (0.2 mmol), CH Cl (2 mL), 40 °C, 6 h.
a
2 3 2
Sonogashira coupling conditions: 3 (0.8 mmol), 4 (0.88 mmol), PdCl (PPh )
b
c
Gold-catalyzed cyclization conditions: i. 1 (0.2 mmol), AuCl(PPh
3
2
2
2
Isolated yield.
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This work was supported by the National Natural Science Foundation
of China/Research Grants Council Joint Research Scheme
(N_CUHK451/13), the Research Grants Council of the Hong Kong SAR,
China (GRF Project 403012), a grant to the State Key Laboratory of
Synthetic Chemistry from the Innovation and Technology Commission,
The Chinese Academy of Sciences–Croucher Foundation Funding
Scheme for Joint Laboratories, and the National Natural Science Foun-
dation of China (NSFC no. 21272199). The Shenzhen Science and
Technology Innovation Committee for the Municipal Key Laboratory
Scheme (ZDSY20130401150914965), and the Shenzhen Basic Research
Program (JCYJ20120619151721025, JCYJ20140425184428455) are
also gratefully acknowledged.
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(
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3
AgOTf (10 mol%) were added to a stirred solution of 1 (0.2
mmol) in CH Cl (2 mL) under nitrogen at room temperature,
and the solution was stirred for 15 min. p-TsOH·H O (0.2 mmol)
was added and the resulting mixture was stirred for 6 h at 40 °C,
then cooled to room temperature and the solvent was removed
under reduced pressure. The resulting residue was purified by
flash column chromatography to give tricyclic chromone 2.
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2
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1461–1464