Lewis Acid-Catalyzed Formal [3+3] Annulation of Propargylic Alcohols with 4-Hydroxy-2H-chromen-2-ones

Article abstract of DOI:10.1002/adsc.201800131

A Lewis acid-catalyzed formal [3+3] cascade annulation strategy for the formation of diverse tricyclic compounds possessing functionalized pyrano[3,2-c]chromen-5(2H)-one fragments has been developed using propargylic alcohols and 4-hydroxy-2H-chromen-2-on

Full text of DOI:10.1002/adsc.201800131

Title: Lewis Acid-Catalyzed Formal [3+3] Annulation of Propargylic
Alcohols with 4-Hydroxy-2H-chromen-2-ones
Authors: Ya-Ping Han, Xue-Song Li, Ming Li, Xin-Yu Zhu, and Yong-
Min Liang
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10.1002/adsc.201800131
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201
Lewis Acid-Catalyzed Formal [3+3] Annulation of Propargylic
Alcohols with 4-Hydroxy-2H-chromen-2-ones
Ya-Ping Han,a Xue-Song Li,a Ming Li,a Xin-Yu Zhu,a Yong-Min Lianga,*
a Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province and State Key Laboratory
of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000,
People,s Republic of China
Fax: +86-931-8912582; e-mail: liangym@lzu.edu.cn
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
is a member of a subclass of HIV-1-specific reverse
transcriptase inhibitors.[5] Due to the importance and
ubiquity of this framework in organic chemistry, the
development of new reliable approaches for the
Abstract. A Lewis acid-catalyzed formal [3+3] cascade
annulation strategy for the formation of diverse tricyclic
compounds
possessing
functionalized
pyrano[3,2-
c]chromen-5(2H)-one fragments has been developed using
propargylic alcohols and 4-hydroxy-2H-chromen-2-ones as
synthesis
of
pyrano[3,2-c]chromen-5(2H)-one
the substrates. The protocol provides
environmentally benign method of accessing a broad range
of pyrano[3,2-c]chromen-5(2H)-one derivatives in
a
one-step,
derivatives has attracted considerable attention. In
2011, Wang et al. reported a palladium-catalyzed
cascade transformation of coumarins and alkynes for
excellent yields under mild conditions and with good
functional-group tolerance. The method is effective on the
gram scale, which highlights the inherent practicality of
this synthetic transformation.
the
construction
of
highly
substituted
cyclopentadiene-fused chromones (Scheme 1a).[6] An
unusual secondary amine-thiourea promoted reaction
for
the
synthesis
of
barbiturate-fused
employing 4-
tetrahydropyrano
derivatives
Keywords: 4-hydroxy-2H-chromen-2-ones; nucleophilic
addition; Lewis acids; alcohols; pyrano[3,2-c]chromen-
5(2H)-one derivatives
hydroxycoumarins and nitroalkenes as the substrates
has been disclosed by the Chen group (Scheme 1b).[7]
Xu and co-workers developed an efficient synthesis
of valuable pyranocoumarins through a gold (III)-
catalyzed tandem annulation of 4-hydroxycoumarins
and α,β-unsaturated ketones. (Scheme 1c).[8] Despite
several methods having been reported,[9] there is still
demand for new methodologies that are more
efficient and environmentally benign for the
generation of pyrano[3,2-c]chromen-5(2H)-one
derivatives.
The pyrano[3,2-c]chromen-5(2H)-one derivatives
represent one of the most important classes of
oxygen-containing compounds because they are
embedded in a wide array of biologically active
natural
products,
pharmaceutically
relevant
molecules, agrochemicals, and key skeletal structures
in organic chemistry and materials science.[1] For
example, the biologically active prenylated coumarin
ferprenin, isolated from Ferulu communis, was
identified as having the ability to cause severe
hemorrhagic disease (Figure 1).[2] Arisugacin A,
which was isolated from the culture broth of
Penicillium sp. Fo-4259, is the most selective and
potent
known
inhibitor
and
against
serum
butyrylcholinesterase
erythrocytes
acetylcholinesterase, and thus, it has therapeutic
significance for the treatment of dementia.[3]
Pyripyropene A, isolated from a fermentation broth
of Aspergillus fumigatus FO-1289 by the Omura
group, showed potent inhibitory activities against
acyl-CoA and cholesterol acyltransferase and has
potential for the prevention and treatment of
Figure 1. Select biologically active natural compounds
that contain this structural motif
atherosclerosis.[4]
(+)-Calanolide
A,
a
dipyranocoumarin isolated by Boyd and co-workers
from the rainforest tree Calophyllum lanigerum var,
1
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10.1002/adsc.201800131
Advanced Synthesis & Catalysis
During the past decade, the rapid development of
Table 1. Optimization of the conditions of the reaction of
1a with 4-hydroxy-2H-chromen-2-one a, b)
Lewis acid-catalyzed cascade annulations has
afforded practical, versatile, and atom-economical
methods of accessing complex heterocycles,
carbocycles and condensed ring scaffolds that are not
easily synthesized by traditional methods. In
particular, Lewis acid-catalyzed annulations of
propargylic alcohols with
a
broad range of
nucleophiles and electrophiles have enabled the
efficient construction of pyrroles,[10] furans,[11]
indoles,[12] pyridines,[13] quinoline,[14] thiazoles,[15]
and azepines.[16] Inspired by these intriguing
discoveries for propargylic alcohols, we herein
describe the development of a zinc-catalyzed formal
[3+3] cascade annulation of propargylic alcohols
with 4-hydroxy-2H-chromen-2-ones, leading to the
facile formation of pyrano[3,2-c]chromen-5(2H)-one
derivatives in excellent yields under mild conditions.
catalyst
(10 mol %)
temp
(°C)
yield
(%)b)
entry
solvent
t (h)
1
2
Y(OTf)3
Yb(OTf)3
Al(OTf)3
Cu(OTf)2
Bi(OTf)3
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
CH3COOH
TFA
THF
THF
80
80
4
4
55
59
18
22
42
65
33
71
67
72
75
72
29
51
62
37
83
49
61
77
53
3
THF
80
4
4
THF
80
4
5
THF
80
4
6
THF
80
4
Scheme 1. Summary of present studies and our proposed
methods of accessing tricyclic compounds
7
THF
60
4
8
THF
100
120
100
100
100
100
100
100
100
100
100
100
100
100
4
9
THF
4
10
11
12
13
14
15
16
17
18
19
20
21
THF
6
THF
8
THF
10
8
THF
THF
8
TsOH
THF
8
TfOH
THF
8
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
DCE
CH3NO2
PhCH3
CH3CN
1,4-dioxane
8
8
8
8
24
a)
Unless otherwise noted, all reactions were performed
with 1a (0.1 mmol) and 4-hydroxy-2H-chromen-2-one 2a
b)
(2.0 equiv.) in solvent (2.0 mL). Yields are given for
isolated products.
We began this investigation by exploring the
reaction between propargylic alcohol (1a) and 4-
hydroxy-2H-chromen-2-one (2a) using several
different combinations of Lewis acid catalysts,
temperature, reaction time, and solvents. To our
delight, desired product 3a was obtained in a
moderate yield of 55% in the presence of a catalytic
amount of Y(OTf)3 (10 mol %) in THF at 80 °C in 4
h in high pressure seal tube (Table 1, entry 1). The
structure of product 3a was unambiguously
determined by NMR spectroscopy and X-ray
crystallography (see the Supporting Information).[17]
Among the different Lewis acid catalysts screened,
Zn(OTf)2 exhibited the best catalytic activity and
gave the desired product in 65% yield (entries 2−6).
Subsequent investigation of the reaction conditions
revealed that 100 °C was optimal for the formal [3+3]
annulation reaction, as it furnished the expected
product in 71% yield (entries 7−9). Moreover, it was
found that the yield improved slightly (to 75%) when
the reaction time was extended to 8 h (entries 10−12).
Due to the reactions were conducted in high pressure
seal tube, a lower temperature and short reaction time
furnished expected product in lower yield. Notably, it
was found that various Brønsted acid catalysts also
performed well and afforded product 3a in moderate
to good yields, indicating that the formal [3+3]
cascade annulation is proposed to proceed via a
nucleophilic substitution pathway (entries 13−16).
Further screening of solvents such as DCE, CH3NO2,
PhCH3, CH3CN, and 1,4-dioxane led to a slightly
higher yield (entries 17−21). Ultimately, the optimal
reaction conditions for the construction of desired
product 3a were the use of alkynol 1a (0.1 mmol),
and 4-hydroxy-2H-chromen-2-one 2a (2.0 equiv.) in
the presence of Zn(OTf)2 (10 mol %) in DCE (2.0
mL) at 100 °C for 8 h in high pressure seal tube.
2
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10.1002/adsc.201800131
Advanced Synthesis & Catalysis
Scheme 2. Conversion of propargylic alcohols into
pyrano[3,2-c]chromen-5(2H)-one derivatives a, b)
With the optimized reaction conditions established,
we next investigated the generality of the scope of
propargylic alcohols for the cascade annulation with
2. As depicted in Scheme 2, the transformation of
various substituted alkynol substrates with 4-
hydroxy-2H-chromen-2-one proceeded smoothly and
delivered the corresponding pyrano[3,2-c]chromen-
5(2H)-one derivatives in moderate to excellent yields.
A wide variety of functional groups, including
methoxy, methyl, ethyl, 3,5-dimethyl, phenyl, cyano,
ester, nitryl, and halogen substituents, were found to
be compatible with the optimized reaction conditions.
In general, aryl substituents with electron-donating
properties (OMe, Me, Et, and 3,5-diMe; 3a−3e) or
electron-withdrawing properties (Ph, CN, COOMe,
and NO2; 3g−3j), at any position on the phenyl ring
(R3), were well-tolerated and afforded the anticipated
products in yields ranging from 61% to 98% (3a−3j).
Various halogen substituents such as F, Cl, and Br on
the aromatic ring (R3) were compatible with the
optimized conditions and generated the desired
products 3k−3m in 92−96% yields. Notably, these
products have the potential for downstream chemical
modifications. Several symmetrical propargylic
alcohols bearing electron-rich (Me and OMe; 3n and
3o) or electron-deficient substituents (F and Cl;
3p−3r) smoothly produced the corresponding
products in 78−95% yields. Various unsymmetrical
propargylic alcohols 1s−1y were then investigated,
and they were well-tolerated in this formal [3+3]
cascade annulation and afforded the anticipated
products 3s−3y in good to excellent yields (74−99%).
However, alkyl-substituted (R3) propargylic alcohols
(1z and 1aa) gave moderate yields or even did not
undergo the desired transformation. This outcome
might be due to the fact that it is difficult for an alkyl
group to stabilize active propargyl intermediate A
generated by alkynol substrate 1 (see Scheme 4). The
R1 and R2 substituents could also be cyclopropyl, and
the corresponding product 3ab was obtained in
moderate yield. Remarkably, the transformation of
secondary propargylic alcohol methyl 4-(3-hydroxy-
3-(p-tolyl)prop-1-yn-1-yl)benzoate (1ac) proceeded
smoothly and allowed the facile construction of
corresponding product 3ac in moderate yield. The 4-
hydroxy-2H-chromen-2-ones
bearing
electron-
donating (Me and OMe) or electron-withdrawing
groups (F, Cl, and Br) on the aromatic ring (R4)
reacted smoothly and generated expected products
5ad−5ah in 88−98% yields.
To evaluate the potential synthetic utility of this
formal [3+3] cascade annulation, the reaction was
carried out on a preparative scale under the standard
reaction conditions, and desired product 3a was
isolated in 71% yield (Scheme 3).
a)
Unless otherwise noted, all reactions were performed
with 1 (0.1 mmol) and 2 (2.0 equiv.) in the presence of
Zn(OTf)2 (10 mol %) in DCE (2.0 mL) at 100 °C for 8 h. b)
Yields are given for isolated products.
Scheme 3. Large-scale experiment
3
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10.1002/adsc.201800131
Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
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5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800131
Advanced Synthesis & Catalysis
COMMUNICATION
Lewis Acid-Catalyzed Formal [3+3] Annulation of
Propargylic Alcohols with 4-Hydroxy-2H-
chromen-2-ones
Adv. Synth. Catal. Year, Volume, Page – Page
Ya-Ping Han, Xue-Song Li, Ming Li, Xin-Yu Zhu,
Yong-Min Liang*
6
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