Phase transfer reagent promoted tandem ring-opening and ring-closing reactions of unique 3-(1-alkynyl) chromones

Article abstract of DOI:10.1021/acs.orglett.5b00721

A phase transfer reagent promoted tandem ring-opening and ring-closing reaction of 3-(1-alkynyl) chromones has been developed. This process remarkably generates functionalized 3-acyl-2-substituted chromones. Interestingly, when 3-(hepta-1,6-diyn-1-yl)chromone derivatives are applied, a novel tetracyclic chromone scaffold can be obtained by a further intramolecular 4 + 2 cyclization.

Full text of DOI:10.1021/acs.orglett.5b00721

Letter
pubs.acs.org/OrgLett
Phase Transfer Reagent Promoted Tandem Ring-Opening and Ring-
Closing Reactions of Unique 3‑(1-Alkynyl) Chromones
Yang Liu,‡,§ Shiyu Jin,‡,§ Liping Huang,‡ and Youhong Hu*,†,‡
†ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of
Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
‡State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi
Road, Shanghai 201203, China
S
* Supporting Information
ABSTRACT: A phase transfer reagent promoted tandem ring-opening and ring-closing reaction of 3-(1-alkynyl) chromones has
been developed. This process remarkably generates functionalized 3-acyl-2-substituted chromones. Interestingly, when 3-(hepta-
1,6-diyn-1-yl)chromone derivatives are applied, a novel tetracyclic chromone scaffold can be obtained by a further intramolecular
4 + 2 cyclization.
Scheme 1. Strategies for the Synthesis of 3-Acyl-2-
substituted Chromones
chromone fragment is a ubiquitous structure that occurs
in a wide variety of naturally occurring1 and synthetic
A
compounds exhibiting various important biological activities.2
Among the chromone derivatives reported, 3-acyl-2-substituted
chromone derivatives display several biological activities such as
antimalarial, anticytochrome P450, and anti-HIV activities.3
Besides, 3-acyl-2-substituted chromones with good photo-
chromic properties have also been reported.4 However, only
a few synthetic approaches have been investigated.5 The 3-acyl-
2-substituted chromone derivatives can usually be prepared in
the conventional synthesis from 2-fluoride or 2-hydroxyaceto-
phenones by a tandem condensation and cyclization reaction at
high temperature5a,c−e (Scheme 1a) with limited functional
derivatives. Recently, Doi and co-workers reported a concise
synthesis of diverse 3-aroylflavones (3-benzoyl-2-phenylchro-
mones) via Lewis base catalyzed tandem acyl transfer−
cyclization5b (Scheme 1b). Our research group has focused
on the functionalized 3-(1-alkynyl)chromones to generate
diversified natural-product-like scaffolds through cascade
reactions.6 Herein, we describe novel phase transfer reagent
promoted tandem ring-opening and ring-closing reactions of
unique 3-(1-alkynyl)chromones with water to construct
diversified 3-acyl-2-benzyl or alkyl chromones with a more
broad scope under mild reaction conditions in good to
excellent yields (Scheme 1c).
formation of 3g involves a domino process as depicted in
Scheme 2. First, M1 could be generated by a Michael addition
of H2O with compound 1g under phase transfer conditions,
along with the pyrone ring-opening to form M2. Subsequently,
the OH anion of M2 can recyclize with the allene bond which
was formed via an alkyne isomerization to produce the
intermediate M3. The protonation of M3 finally leads to the
formation of the 3-acetyl-2-(4-cyanobutyl) chromone 3g.
Notably, with only the n-Bu4NCl additive this tandem process
does not precede the known cyclization to form a furan,
In our earlier studies of the phenylacetonitrile modulated
cyclization with 3-(1-alkynyl)chromones (Scheme 2),6b we
found the desired product 2 in 10% yield with 3-acetyl-2-(4-
cyanobutyl) chromone 3g in 62% yield while phenylacetonitrile
was replaced by n-Bu4NCl (TBAC). We envisioned that the
Received: March 12, 2015
Published: April 22, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00721
Org. Lett. 2015, 17, 2134−2137

Organic Letters
Letter
irradiation, the desired product 3a was isolated in 40% yield
(Table 1, entry 1). When 10 equiv of H2O were added, the
yield of the reaction increased to 63% (Table 1, entry 2). This
result supports our proposed mechanism that H2O is involved
in the Michael addition with 1a. In the presence of water, t-
BuOK could be converted to KOH. When using 2 equiv of
saturated solution of KOH instead of 2 equiv of t-BuOK and 10
equiv of H2O (Table 1, entry 3), the desired product 3a was
obtained in 33% yield. By changing the solvent to t-BuOH, the
yield increased to 52% (Table 1, entry 4). To our delight, the
yield of 3a further increased to 76% by carrying out the reaction
at room temperature for 3 h (Table 1, entry 5). When reducing
the phase transfer reagent TBAC to 1 or 0.5 equiv, the tandem
reaction yielded 3a in 68% yield (Table 1, entries 6 and 7). It
indicates the reaction could be catalyzed by the transfer reagent.
Reducing the phase transfer reagent TBAC to 0.2 equiv could
decrease the reaction yield apparently (Table 1, entry 8).
Subsequently, among the different phase transfer reagents
explored, TBAC is the best (Table 1, entries 9−11). Also, by
reducing the base to 1 equiv, the yield of product deceased to
33% (Table 1, entry 12). An exploration of different solvents
uncovered the observation that t-BuOH is more suitable for this
tandem process (Table 1, entries 13−17). In summary,
optimized conditions involve reaction in t-BuOH at room
temperature for 3 h in the presence of 2.0 equiv of n-Bu4NCl
(TBAC) and a saturated solution of KOH respectively.
Scheme 2. Plausible Mechanism for the Formation of 3g
furocoumarin, or xanthone scaffold as reported before.6 This is
a novel efficient synthetic approach to generate functional 3-
acyl-2-substituted chromone derivatives via a tandem reaction
of 3-(1-alkynyl)-chromones.
Based on the above results, we examined this tandem
reaction with 2-methyl-3-(phenylethynyl) chromone 1a using
different conditions (Table 1). When the reaction was carried
out in the presence of 2.0 equiv of t-BuOK and n-Bu4NCl
(TBAC) in DMF at 110 °C for 10 min under microwave
Table 1. Optimization of Reaction Conditions for the
a
Formation of 3-Acyl-2-substituted Chromone 3a
To extend the scope of this tandem reaction, various
substrates of 1 were used (Scheme 3). When R1 was an
aromatic group on the acetylene moiety, products 3a−3c were
obtained in 54−76% yields. It was noted that an electron-
withdrawing group on the aromatic ring was unfavorable in the
d
entry
1
additive
base; solvent
temp
yield(%)
40
TBAC (2.0 equiv) t-BuOK; DMF
110 °C;
10 min
b
2
TBAC (2.0 equiv), t-BuOK; DMF
H2O
110 °C;
10 min
63
a
Scheme 3. Synthesis of 3-Acyl-2-substituted Chromones 3
3
TBAC (2.0 equiv) KOH(sat.soln);
110 °C;
10 min
33
DMF
4
TBAC (2.0 equiv) KOH(sat.soln);
t-BuOH
110 °C;
10 min
52
5
TBAC (2.0 equiv) KOH(sat.soln);
t-BuOH
rt; 3 h
rt; 3 h
rt; 3 h
rt; 3 h
rt; 3 h
rt; 3 h
rt; 3 h
rt; 3 h
rt; 3 h
rt; 3 h
rt; 3 h
rt; 3 h
76
6
TBAC (1.0 equiv) KOH(sat.soln);
t-BuOH
68
7
TBAC (0.5 equiv) KOH(sat.soln);
t-BuOH
68
8
TBAC (0.2 equiv) KOH(sat.soln);
t-BuOH
28
9
TBAF (0.5 equiv) KOH(sat.soln);
t-BuOH
50
10
11
TBAB (0.5 equiv) KOH(sat.soln);
t-BuOH
20
TBAI (0.5 equiv) KOH(sat.soln);
t-BuOH
22
c
12
TBAC (0.5 equiv) KOH(sat.soln);
t-BuOH
33
13
14
15
16
17
TBAC (2.0 equiv) KOH(sat.soln);
12
EtOH
TBAC (2.0 equiv) KOH(sat.soln);
64
isopropanol
TBAC (2.0 equiv) KOH(sat.soln);
trace
13
DMSO
TBAC (2.0 equiv) KOH(sat.soln);
dioxane
TBAC (2.0 equiv) KOH(sat.soln); THF rt; 3 h
trace
a
Unless otherwise noted, reactions were carried out with 1a (0.5
b
mmol) and 2 equiv of base. The reaction was carried out with 10
c
a
equiv of H2O. The reaction was carried out with 1 equiv of KOH.
Unless otherwise noted, reactions were carried out under the
d
Yield of isolated product based on 1a.
optimized reaction conditions; isolated yield.
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DOI: 10.1021/acs.orglett.5b00721
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Organic Letters
Letter
a
domino process. The reactions also proceeded smoothly when
R1 was a heterocycle or an aliphatic chain. However, there are
obvious electronic effects on the R2 substituent. When R2 was
an electron-donating group, the desired product 3i could be
obtained in good yield. An electron-withdrawing group such as
a Br substituent could reduce the nucleophilicity of the oxygen
anion for the ring-closing process and decrease the yield of the
product. In addition, when R3 was an ethyl, isopropyl, or phenyl
group, the desired products were obtained in excellent yields
respectively, which indicated that the steric effects of the R3
position did not influence this tandem process. Finally, when R3
was hydrogen, a product containing a formyl group was also
achieved successfully in moderate yield. Recently, Siegel and co-
workers reported a similar reaction to form the aldehyde
intermediates for the synthesis of Vinaxanthone and its
derivatives through ynone coupling reactions.7
Table 2. Synthesis of Novel Tetracyclic Chromones 4
In order to expand further application of this ring-opening
and ring-closing tandem reaction, we envisioned that substance
1m might undergo a further intramolecular 4 + 2 cyclization to
afford M6,7 which then could be transformed to a novel
tetracyclic chromone scaffold via an aromatization (Scheme 4).
Scheme 4. Proposed Mechanism To Form Novel Tetracyclic
Chromone Scaffold
a
Unless otherwise noted, reactions were carried out under the
optimized reaction conditions; isolated yield.
reactions also proceed smoothly when R3 was H (Table 2, entry
5). However, when R3 was a phenyl group (Table 2, entry 6),
the desired product was obtained in low yield, which may due
to the steric effect of two phenyl groups at the ortho-position.
In conclusion, a novel and efficient phase transfer reagent
promoted tandem ring-opening and ring-closing reaction of 3-
(1-alkynyl)chromones with H2O has been developed for the
generation of functionalized 3-acyl-2-substituted chromones.
This cascade process is mild and has a broad scope without the
need for a transition metal catalyst. It is an efficient supplement
for the synthetic approaches of diverse 3-acyl-2-substituted
chromones which may be applied in drug discovery and
materials engineering. Meanwhile, this tandem reaction has also
been further explored to construct novel tetracyclic chromones
via an anion transfer reagent, which included phenylacetonitrile
modulating further cyclization reactions. Further library
generation and biological evaluation of the diversified 3-acyl-
2-substituted chromones and tetracyclic chromones are under
investigation.
After brief work designed to examine the reaction conditions
for the formation of novel tetracyclic chromone 4a (see
Supporting Information, Table S1), the optimized reaction
conditions were determined to involve 2.0 equiv of t-BuOK,
using 2.0 equiv of n-Bu4NCl in place of n-Bu4NF, and 1.0 equiv
of phenylacetonitrile 5 as an anion transfer reagent6b in DMSO
at 110 °C for 20 min under microwave irradiation. Additionally,
the structure of 4a was unambiguously established by X-ray
crystal structure analysis (Figure 1).8
Figure 1. X-ray structure of tetracyclic chromone 4a.7
Subsequently, the scope of this reaction was explored under
the optimized reaction conditions, and the results were
displayed in Table 2. We obtained the desired novel tetracyclic
chromone derivatives mostly in good yields. There are no
obvious electronic effects on an aromatic group of R4 (Table 2,
entries 1−3). But when R4 was H, the corresponding product
4d was found in 40% yield (Table 2, entry 4). Notably, the
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and spectral data for all new compounds
and crystal structure data for 4a in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
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DOI: 10.1021/acs.orglett.5b00721
Org. Lett. 2015, 17, 2134−2137

Organic Letters
Letter
(e) Xie, F.; Pan, X.; Lin, S.; Hu, Y. Org. Biomol. Chem. 2010, 8, 1378.
(f) Liu, Y.; Huang, L.; Xie, F.; Hu, Y. J. Org. Chem. 2010, 75, 6304.
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(8) CCDC 1038732 (4a) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yhhu@zju.edu.cn.
Author Contributions
§Y.L. and S.J. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support of this research provided by National Natural
Science Foundation of China (81225022) and (21172232) is
gratefully acknowledged.
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