One-pot reaction of ortho-acylphenols and terminal alkynoates for synthesis of 2-alkyl-substituted chromanones

Article abstract of DOI:10.1016/j.tetlet.2010.01.093

A facile synthesis of 2-alkyl-substituted chromanones from ortho-acylphenols and terminal alkynoates is described. The method contains two consecutive processes in one-pot reaction through a DABCO-catalyzed condensation reaction and a KOBu^t-mediated intramolecular cycloaddition to afford the desired products.

Full text of DOI:10.1016/j.tetlet.2010.01.093

Tetrahedron Letters 51 (2010) 1748–1750
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Tetrahedron Letters
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One-pot reaction of ortho-acylphenols and terminal alkynoates for synthesis
of 2-alkyl-substituted chromanones
Ling-Guo Meng b, Hui-Fang Liu a, Jian-Long Wei a, Sun-Na Gong a, Song Xue a,
*
a Department of Applied Chemistry, Tianjin University of Technology, Tianjin 300191, China
b Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile synthesis of 2-alkyl-substituted chromanones from ortho-acylphenols and terminal alkynoates is
described. The method contains two consecutive processes in one-pot reaction through a DABCO-cata-
lyzed condensation reaction and a KOBut-mediated intramolecular cycloaddition to afford the desired
products.
Received 21 December 2009
Revised 16 January 2010
Accepted 26 January 2010
Available online 1 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Structuralmotifswhichare observedin manynaturally occurring
organic compound possessing varying biological activities have
come to be known as ‘privileged structures’.1 The chromanone is
one of the important scaffold that can be obtained from natural com-
pounds exhibiting favorable pharmacological properties such as
antioxidant, antitumour, antibacterial activities.2 They have also
used as key intermediates in the synthesis of chromone derivatives.3
Consequently, great efforts have been devoted to the synthesis of
this privileged structure.4 Generally, most of synthetic methods
are known to produce chromanone derivatives by carrying an aryl
substituent in the 2-position, so-called flavanones.5 But these condi-
tions are not suitable for the preparation of 2-alkyl-substituted 4-
chromanones.3 To the best of our knowledge, there were limited
methods to synthesize 2-alkyl-substituted chromanone derivatives
in previous reports.6 However, these compounds are commonly ob-
tained under harsh conditions or by multi-step reaction. In order to
circumventthese problems, thedevelopment of aneasy and efficient
method for 2-alkyl-substituted chromanones has been strongly
desired.
In recent years, one of the rapidly growing research areas in the
field of organic synthesis is that of application of organic base to cat-
alyze reactions based on the electron-deficient alkynes or alkenes.7
In our group, we are interested in the application of organic bases
catalyzed cycloaddition reactions based on electron-deficient al-
kynes.8 Recently, we have reported PPh3-catalyzed cycloaddition
of 1-(o-hydroxyaryl)-3-alkyl-1,3-diketones to ethyl propiolates to
provide various chromone derivatives (Scheme 1).9 As a continua-
tion of annulation reaction research, we further investigate the pos-
sibility of cyclization reaction of ortho-acylphenols with terminal
alkynoates. To our delight, a chromanone derivative was formed
by two consecutive reaction processes: (1) condensation of ortho-
acylphenol with ethyl propiolate in the presence of 1,4-diazabicy-
clo[2,2,2]-octane (DABCO); (2) followed by addition of KOBut to
accomplish intramolecular cyclization. Herein, we wish to report
this facile one-pot synthetic method of 2-alkyl-substituted chroma-
nones starting from commercial available materials.
The reaction of 2-hydroxyacetophenone 1a with ethyl propio-
late 2a was carried out in the presence of DABCO (10 mol %) in
N,N-dimethylformamide (DMF) at room temperature for 0.5 h,10
followed by addition of 1.2 equiv KOBut in a one-pot manner under
various conditions, and the results were shown in Table 1. The
functionalized 2-alkyl-substituted chromanone 3a was obtained
in 65% yield when the reaction was stirred for another 2 h at room
temperature after addition of KOBut (Table 1, entry 2). Its structure
was determined by NMR and HRMS spectra. Surprisingly, only a
trace amount of the product 3a was observed when DABCO and
KOBut were added simultaneously to the reaction. A small amount
of 3a (<10%) was afforded when the reaction was performed at
60 °C (Table 1, entry 5). However, the yield of the product was
unsuccessfully improved by reducing the reaction temperature
from room temperature to 0 °C (Table 1, entry 4). On the other
hand, other inorganic bases, in place of KOBut, were examined
and had significant influence on the reaction. The application of
NaH to the reaction afforded 3a with comparable yield (Table 1,
entry 6). Compared with KOBut, KOH afforded the product with
lower yield (43%) (Table 1, entry 7). With the utilization of NaOEt
O
OH
O
O
O
PPh3 (30 mol%)
CH2Cl2, 0°C, 24h
COOEt
R1
+
OEt
O
R1
R1 = alkyl
* Corresponding author. Tel.: +86 22 60214250.
E-mail address: xuesong@ustc.edu.cn (S. Xue).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.093

L.-G. Meng et al. / Tetrahedron Letters 51 (2010) 1748–1750
1749
Table 1
Table 2
Optimization of the reaction conditions
Reactions of ortho-acylphenols 1 with electron-deficient alkynes for synthesis of
2-alkyl-substituted chromanones
O
OH
O
O
DABCO (10 mol%), 0.5 h
KOBut (1.2 equiv), 2 h
rt, DMF
O
+
Entry
1
Substrate
Product, yielda
OEt
COOEt
R2
O
OH
O
O
2a
1a
3a
COOEt
EtO
EtO
Entry
Base
Solvent
Yielda (%)
3a: 65%
1a
O
O
1
2
3
4
5
6
7
8
9
KOBut
KOBut
KOBut
KOBut
KOBut
NaH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
62b
65
OH
O
COOEt
52c
58d
<10e
64
Me
2
3
4
3b: 72%
O
1b
O
Me
OH
O
KOH
43
COOEt
EtONa
K2CO3
KOBut
KOBut
KOBut
DMF
DMF
CH3CN
Toluene
CH2Cl2
<10
NRf
37
22
<10
MeO
EtO
EtO
EtO
10
11
12
3c: 72%
O
1c
O
OMe
OH
O
COOEt
a
b
c
d
e
f
Isolated yield.
Performed for 1 h.
Performed for 4 h.
At 0 °C.
At 60 °C.
NR = no reaction.
3d: 51%
O
1d
O
OEt
OH
O
COOEt
5
6
EtO
EtO
OMe
3e: 61%
OMe O
MeO
1e
or K2CO3, the yields of the reaction gave bad results (Table 1, en-
tries 8 and 9). Further investigation conducted with a solvent
screen and a significant solvent effect was observed. When shifting
solvent to CH3CN or toluene, the desired product 3a was afforded
in 37% and 22% (Table 1, entries 10 and 11), respectively. With
CH2Cl2 as solvent, the yield of the reaction was produced in a rel-
atively low yield (Table 1, entry 12).
OH
O
O
COOEt
MeO
3f: 62%
O
1f
OH
O
O
COOEt
Cl
Cl
7
8
EtO
EtO
Under these optimized conditions,11 we next explored the scope
of one-pot synthesis of 2-alkyl-substituted chromanones 3. As
shown in Table 2, a variety of ortho-acylphenols 1 were employed
as reaction substrates and the reaction can afford the correspond-
ing chromanone derivatives in moderate to good yields regardless
of the different substitutions on aromatic ring of ortho-acylphenol.
Clearly, substrate with an electron-donating group on the aromatic
ring gave better yield than that of an electron-withdrawing group
on the aromatic ring. For example, substrates with methyl, meth-
oxy or ethoxy group, the yields of corresponding products were
afforded in good yields (Table 2, entries 2–6). While the substrate
with a chloro group in the phenyl ring gave the corresponding
product in moderate yield, a low yield of 25% was obtained under
typical conditions when naphthyl substrate 1i was submitted to
the reaction. After optimized conditions for this substrate, 53%
yield of 3i was obtained when the reaction of substrate 1i with
ethyl propiolate was performed in the presence of DABCO for 4 h,
followed by addition of KOBut with stirring for another 0.5 h (Table
2, entry 9). Notably, the multi-substituted ortho-acylphenols, such
as 1k and 1l, also reacted smoothly to give the corresponding prod-
ucts in moderate yields. But the reaction became complex when 1-
(2-hydroxyphenyl)propan-1-one 1m was used as substrate, which
might be due to steric hindrance. On the other hand, when other
electron-deficient alkynes, such as methyl propiolate, but-3-yn-
2-one, and 1-phenylprop-2-yn-1-one, were applied into the reac-
tion, the corresponding products were given in moderate to good
yields.
O
O
3g: 42%
1g
Cl
OH
O
COOEt
Cl
O
3h: 41%
1h
OH
O
COOEt
O
b
9
EtO
O
1i
3i: 25% (53%)b
O
O
COOEt
O
c
OH
O
10
11
EtO
EtO
3j: 32% (58%)c
1j
OH
Me
Me
O
COOEt
3k: 76%
Me
Br
O
O
1k
O
Me
OH
Br
COOEt
Me
12
EtO
3l: 38%
O
1l
Me
O
OH
13
14
EtO
Complex
1m
O
The proposed mechanism for the formation of 2-alkyl-substi-
tuted chromanone 3 is shown in Scheme 2. Ortho-acylphenol 1 is
added to ethyl propiolate via Michael-type reaction catalyzed by
DABCO to give enol ether 4.10 The enol ether 4 will undergo an intra-
molecular cycloaddition mediated by KOBut to generate intermedi-
OH
O
COOMe
MeO
1a
3m: 66%
O

1750
L.-G. Meng et al. / Tetrahedron Letters 51 (2010) 1748–1750
Table 2 (continued)
Acknowledgments
O
We are grateful to the National Natural Science Foundation of
China (20772116) and the Tianjin Natural Science Foundation
(09JCZDJC24400) for financial supports.
Entry
15
Substrate
Product, yielda
R2
OH
O
O
Me
O
Me
Supplementary data
1a
3n: 59%
O
O
OH
O
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.01.093.
16
C6H5
O
1a
References and notes
3o: 40%
O
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b
The reaction of substrate 1i with ethyl propiolate was performed in the pres-
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c
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OH
O
O
COOEt
DABCO
COOEt
COOEt
+
O
R
R
O
4
1
2a
KOBut
O
O
O
COOEt
COOEt
R
R
R
O
3
O
6
5
Scheme 2. Possible mechanism for the formation of chromanone derivative 3.
O
O
O
KOBut
O
O
DMF, 2 h, rt
R2
R2
O
3a: 66%
3n: 61%
4a: R2 = OEt
4n: R2 = Me
Scheme 3. The intramolecular cycloaddition of enol ethers mediated by KOBut.
ate 6, which could be subsequently hydrolyzed to give the desired
product 3. In order to further understand the reaction procedure,
enol ethers 4a and 4n were synthesized from the reaction of
2-hydroxyacetophenone 1a with electron-deficient alkynes in the
presence of DABCO. The reaction of 4a and 4n mediated by KOBut
in DMF at room temperature did give the expected products 3a
and 3n in 66% and 61% isolated yields, respectively, as shown in
Scheme 3.
In summary, we have developed a facile one-pot synthetic
method of 2-alkyl-substituted chromanones starting from com-
mercially available ortho-acylphenols. With the application of this
synthetic method, a series of chromanone derivatives were pre-
pared in moderate to good yields.
9. Meng, L.-G.; Hu, B.; Wu, Q.-P.; Liang, M.; Xue, S. Chem. Commun. 2009, 6089–
6091.
10. Fan, M.-J.; Li, G.-Q.; Li, L.-H.; Yang, S.-D.; Liang, Y.-M. Synthesis 2006, 14, 2286–
2292.
11. General reaction procedure: To a solution of ortho-acylphenols (0.5 mmol) and
terminal alkynoates (0.6 mmol) in DMF was added DABCO (0.05 mol, 6 mg),
and the resulting mixture was performed at room temperature for 0.5 h.
Subsequently, KOBut (0.6 mmol, 70 mg) was added and the reaction was
stirred for another 2 h. Then the reaction was quenched by ice water and
extracted with CH2Cl2 (3 Â 10 mL). The combined organic layers were washed
with brine and then dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo to give crude products, which were purified by column
chromatograph packed with silica gel using petroleum ether/ethyl acetate
(20:1) as eluent to afford the pure products.