Br?nsted Acid-Mediated Formal [3+3] Annulation Between Propargylic Alcohols and 1,3-Diketones

Article abstract of DOI:10.1002/adsc.201701296

A Br?nsted acid-mediated formal [3+3] cascade annulation of propargylic alcohols with 1,3-diketones proceeds through a sequential Meyer?Schuster rearrangement/1,2-addition. This protocol, which has a wide scope and is conducted under an ambient atmosphere

Full text of DOI:10.1002/adsc.201701296

Title: Brønsted Acid-Mediated Formal [3+3] Annulation Between
Propargylic Alcohols and 1,3-Diketones
Authors: Ya-Ping Han, Xue-Song Li, Xin-Yu Zhu, Zhou Sun, Ming Li,
Yu-Zhao Wang, and Yong-Min Liang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701296
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10.1002/adsc.201701296
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201
Brønsted Acid-Mediated Formal [3+3] Annulation Between
Propargylic Alcohols and 1,3-Diketones
Ya-Ping Han, Xue-Song Li, Xin-Yu Zhu, Zhou Sun, Ming Li, Yu-Zhao Wang, Yong-
Min Liang*
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######.
pyranyl heterocycles using 1,3-cyclohexanediones and
Abstract. A Brønsted acid-mediated formal [3+3] cascade
annulation of propargylic alcohols with 1,3-diketones α, -unsaturated aldehydes as the substrates (Scheme
1a).[5] Three-component reactions of aromatic
aldehydes with 1,3-cyclohexanediones and indoles for
the facile assembly of the corresponding products
using L-proline as the catalyst have been developed by
the Gu group (Scheme 1b).[6] Recently, McGlacken
and co-workers reported an elegant protocol for the
synthesis of oxoisochromene derivatives through an
intramolecular, one-step arylation of ,-unsaturated
ketones (Scheme 1c).[7] Therefore, the search for
practical and convenient synthetic approaches for the
generation of chromenone derivatives from easily
prepared starting materials is still an attractive target
for synthetic organic chemists.
proceeds
through
a
sequential
Meyer−Schuster
rearrangement/1,2-addition. This protocol, which has a wide
scope and is conducted under an ambient atmosphere,
enables access to a broad array of valuable chromenone
derivatives related to many natural products in satisfactory
yields under mild conditions. This method could be scaled
up to the gram scale, which highlights the latent applicability
of this transformation.
Keywords: Brønsted acid-mediated; propargylic alcohols;
1,3-diketones; formal [3+3] cascade annulation;
chromenone derivatives
Chromenone derivatives, which belong to an important
class of oxygen-containing compounds, have been
found to have numerous biological and
pharmacological activities and serve as key
intermediates in organic synthesis and functional
materials science.[1] For example, the natural product
ferprenin, which is a prenylated coumarin from Ferulu
communis, was identified as the causative agent of a
serious hemorrhagic disease (Figure 1).[2] Arisugacin
H, isolated from the culture broth of Penicillium,
exhibits inhibitory activities against human
erythrocytes acetylcholinesterase and horse serum
butyrylcholinesterase and has potential as a treatment
for Alzheimer disease.[3] Tetrahydrocannabinol (THC)
and cannabivarin (CBV), plant cannabinoids isolated
from Cannabis sativa, are believed to hold therapeutic
promise in various pathological conditions and
diseases, ranging from anxiety disorders, inflammation,
central nervous system disorders, myocardial
infarction, to Huntington’s disease.[4] Thus, the
Figure
compounds
1.
Representative
chromenone-containing
1,3-Dicarbonyl derivatives have been extensively
used as important synthetic intermediates because they
incorporate
nucleophilic
and
electrophilic
functionalities.[8] In particular, the use of 1,3-
dicarbonyl derivatives as nucleophilic or electrophilic
reagents for the construction of structurally diverse
oxygen-containing compounds, such as pyrroles,[9]
indoles,[10] dihydropyrans,[11] tetrahydroindolizines,[12]
development
of
versatile,
efficient,
and
environmentally benign tandem procedures and
alternative methods for the construction of
chromenone derivatives has attracted much attention.
In 2014, Li et al. reported a novel hollow-structured
ZIF-8-H nanosphere-catalyzed syntheses of valuable
dihydrofurans,[13]
-hydroxyesters,[14]
-
alkylidenebutenolides,[15]
and
olefinic
1
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10.1002/adsc.201701296
Advanced Synthesis & Catalysis
cyclopentanes,[16] has been widely investigated.
Inspired by these intriguing reports and our continued
interest in the transformations of propargylic alcohols,
we herein report a novel Brønsted acid-mediated
formal [3+3] annulation system involving reactions of
propargylic alcohols with 1,3-diketones, which enables
an efficient, single-step, atom-economical synthesis of
chromenone derivatives under mild conditions.
tem
p
(°C)
entr
y
yield
(%)b)
catalyst (equiv)
solvent
t (h)
1
2
BF3Et2O (1.0)
TMSCl (1.0)
TsOH (1.0)
HCOOH(1.0)
CH3COOH(1.0)
TFA (1.0)
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DCE
80
8
8
17
21
27
12
19
65
46
71
69
75
77
68
49
84
54
52
60
38
11
Scheme 1. Summary of current methods and our proposed
pathway toward chromenone derivatives
80
80
3
8
4
80
8
5
80
8
6
80
8
7
TFA (1.0)
60
8
8
TFA (1.0)
100
120
100
100
100
100
100
100
8
9
TFA (1.0)
8
10
11
12
13
14
15
16
17
18
19
TFA (1.0)
16
24
32
24
24
24
24
24
24
24
TFA (1.0)
TFA (1.0)
TFA (0.2)
TFA (0.5)
TFA (0.5)
At the outset, alkynol substrate 3-(4-
methoxyphenyl)-1,1-diphenylprop-2-yn-1-ol (1a) and
cyclohexane-1,3-dione (2a) were chosen as the model
substrates for the optimization of the reaction
conditions. Gratifyingly, desired product 3a could be
obtained in 17% yield when the reaction was
conducted with one equivalent of BF3Et2O (1.0 equiv)
in THF at 80°C for 8 h (Table 1, entry 1). Notably,
various Brønsted acid catalysts were also screened in
this cyclization reaction, and TFA was found to have
the best catalytic activity; it furnished desired product
3a in 65% yield (entries 2−6). Further screening of the
temperature revealed that 100°C was most suitable for
the formal [3+3] annulation reaction, and gave 71%
yield of the desired product (entries 7−9). The product
yield was increased to 77% by prolonging the reaction
time to 24 h (entries 10−12). By decreasing the amount
of the Brønsted acid (TFA) to 0.5 equiv, the yield
increased from to 77% to 84% (entries 13−14). The
reaction in various solvents such as DCE, 1,4-dioxane,
toluene, acetonitrile and CH3NO2 did not result in any
improvement in the yield (entries 15−19). Ultimately,
the optimized conditions for the generation of 3a were
defined with the use of 1a (0.1 mmol), cyclohexane-
1,3-dione 2a (3.0 equiv.) in the presence of TFA (0.5
equiv) in THF (2.0 mL) at 100°C for 24 h.
TFA (0.5)
1,4-dioxane 100
TFA (0.5)
PhCH3
CH3CN
CH3NO2
100
100
100
TFA (0.5)
TFA(0.5)
a) Unless otherwise noted, all reactions were performed with
1a (0.1 mmol) and cyclohexane-1,3-dione 2a (3.0 equiv.) in
solvent (2.0 mL). b) Yields are given for isolated products.
group (3f), were well tolerated in the transformation
and furnished the corresponding products in yields
ranging from 42% to 84%. The structure of product 3c
was elucidated by NMR spectroscopy and X-ray
crystal analysis (see the Supporting Information).[17]
When halogen substituents, F, Cl, and Br are present
on the phenyl ring of R3, the reaction proceeded
smoothly and delivered the corresponding products
3g−3i in moderate yields; these substituents allow
easier downstream chemical modifications of these
products. Notably, symmetrical propargylic alcohols
possessing two methyl groups or two fluoride groups
were compatible with the reaction conditions and
afforded desired products 3j and 3k, in 86% and 37%
yields, respectively. Regarding unsymmetrical
alkynols bearing either electron-donating (OMe or Me)
or electron-withdrawing groups (F or Ph) on the
aromatic rings (R1 or R2), the [3+3] cascade annulation
efficiently produced the corresponding products in
60−91% yields (3l−q). The presence of heterocyclic
substituents, for example, thienyl and cyclopropyl
groups, on the propargylic alcohols afforded the
anticipated products 3r and 3s with yields ranging from
58% to 61%. Notably, the reaction of secondary
propargylic alcohol 1-(4-(tert-butyl)phenyl)-3-(4-
With the optimized reaction conditions established,
the scope of the propargylic alcohol substrates of this
formal [3+3] cascade annulation with respect to 2 was
then evaluated, and the results are shown in Scheme 2.
Both electron-rich aryl substituents, such as methoxy,
methyl, ethyl, and 3,5-dimethyl groups (3a−3e), and
electron-deficient aryl substituent, such as a phenyl
Table 1. Optimization of the conditions for the reaction of
1a with cyclohexane-1,3-dione a, b)
methoxyphenyl)prop-2-yn-1-ol
(1t)
gave
2
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10.1002/adsc.201701296
Advanced Synthesis & Catalysis
corresponding product 3t in moderate yield. Taking the
protocol a step further, we sought to examine the scope
of the reaction with respect to the 1,3-diketone.
Cyclopentane-1,3-dione could be used as the 1,3- efficiently be scaled up to grams quantities using the
diketone substrate, and the corresponding [3+3] optimal conditions, and desired product 3a was
annulation products 3u and 3v were obtained in obtained in good yield (75%), which highlights the
moderate yields. Remarkably, the reactions of potential applications of this transformation (Scheme
propargylic alcohol 1a with various substituted 3).
cyclohexane-1,3-diones 2 proceeded well, allowing the
Based on our previously work and the published
facile generation of chromenone derivatives in literature,[18,19] a plausible mechanistic pathway for this
generally moderate to good yields. Cyclohexane-1,3- [3+3] cascade annulation reaction was proposed as
diones containing electron-rich (5-methyl, 5,5- shown in Scheme 4. Initially, the dehydration of
dimethyl, or 5-isopropyl) or electron-deficient (5- propargylic alcohol 1 affords propargyl cation
phenyl) substituents were suitable substrates for this intermediate A, which could furnish resonance-
protocol and led to the respective products 3w−3z in stabilized intermediate B via a Meyer-Schuster
yields ranging from 68% to 83%.
rearrangement in the presence of TFA. Subsequently,
cyclohexane-1,3-dione 2a undergoes tautomerization
Scheme 2. Transformations of propargylic alcohols to to yield intermediate C via an intermolecular
chromenone derivatives a, b)
nucleophilic attack. Intermediate C forms intermediate
D by the release of a proton, which will be captured by
a proton to give intermediate E. Finally, desired
product 3 is generated through intramolecular
nucleophilic attack of the carbon ion site with the
release of a proton.
Scheme 4. Proposed mechanism for the formation of
chromenone derivatives.
In summary, a simple method for the efficient
assembly of functionalized chromenone derivatives by
employing a TFA-mediated formal [3+3] cascade
annulation of propargylic alcohols with 1,3-diketones
has been developed. The developed reaction system is
tolerant of a wide scope of propargylic alcohols and
1,3-diketones. The cost-effective catalytic system,
good functional group compatibility, ambient reaction
conditions, and operational simplicity inherent to this
strategy are salient features of this transformation.
a) Unless otherwise noted, all reactions were performed with
1 (0.1 mmol) and 2 (3.0 equiv.) in the presence of TFA (50
mol %) in THF (2.0 mL) at 100°C for 24 h. b) Yields are
given for isolated products.
Experimental Section
General procedure for the synthesis of 4-(4-
methoxyphenyl)-2,2-diphenyl-7,8-dihydro-2H-chromen-
5(6H)-one (3a)
The reaction of propargylic alcohol 1a (31.4 mg, 0.1 mmol),
cyclohexane-1,3-dione 2a (3.0 equiv), TFA (50 mol %) in
THF (2.0 mL) was conducted at 100°C under an air
atmosphere for 24.0 h. The reaction was completed by TLC
monitoring. The resulting mixture was cooled down to room
temperature. The mixture was evaporated under reduced
pressure. The residue was further purified by
chromatography on silica gel (petroleum ether/ethyl acetate,
5:1) to afford 34.2 mg of 3a.
An advantage of our developed reaction system was
that the [3+3] cascade annulation reactions could
Scheme 3. Large-scale experiment
3
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10.1002/adsc.201701296
Advanced Synthesis & Catalysis
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4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701296
Advanced Synthesis & Catalysis
COMMUNICATION
Brønsted Acid-Mediated Formal [3+3] Annulation
Between Propargylic Alcohols and 1,3-Diketones
Adv. Synth. Catal. Year, Volume, Page – Page
Ya-Ping Han, Xue-Song Li, Xin-Yu Zhu, Zhou
Sun, Ming Li, Yu-Zhao Wang, Yong-Min Liang*
5
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