Cyclization reaction of 2-azido-1-(2-hydroxyphenyl)ethanones with terminal alkynoates catalyzed by 4-dimethylaminopyridine (DMAP): Synthesis of 2-aminobenzofuran-3(2H)-one derivatives

Article abstract of DOI:10.1002/ejoc.201100250

An unexpected cyclization reaction of 2-azido-1-(2-hydroxyphenyl)ethanones with terminal alkynoates catalyzed by 4-dimethylaminopyridine (DMAP) was developed, and 2-aminobenzofuran-3(2H)-one derivatives were obtained in moderate to good yields under mild

Full text of DOI:10.1002/ejoc.201100250

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100250
Cyclization Reaction of 2-Azido-1-(2-hydroxyphenyl)ethanones with Terminal
Alkynoates Catalyzed by 4-Dimethylaminopyridine (DMAP): Synthesis of
2-Aminobenzofuran-3(2H)-one Derivatives
Ling-Guo Meng,[a] Ni-Lin Ge,[a] Ming-Ming Yang,[a] and Lei Wang*[a,b]
Keywords: Oxygen heterocycles / Alkynes / Fused-ring systems / Cyclization
An unexpected cyclization reaction of 2-azido-1-(2-hydroxy-
phenyl)ethanones with terminal alkynoates catalyzed by 4-
dimethylaminopyridine (DMAP) was developed, and 2-
aminobenzofuran-3(2H)-one derivatives were obtained in
moderate to good yields under mild reaction conditions
within 2 h. The scope and limitations of the cyclization reac-
tions were also investigated.
dition of 1-(o-hydroxyaryl)-3-alkyl-1,3-diketones with ethyl
propiolate to provide various chromone derivatives
(Scheme 2).[8] In continuation of our interest in developing
new annulation reactions, the possibility of 2-azido-1-(2-hy-
droxyphenyl)ethanones to undergo cyclization with ter-
minal alkynoates catalyzed by organic bases was investi-
gated. To our delight, an unexpected transformation re-
sulting in 2-aminobenzofuran-3(2H)-one derivatives oc-
curred in the presence of 4-dimethylaminopyridine
(DMAP). To date, there is a general lack of simple pro-
cedures to synthesize 2-aminobenzofuran-3(2H)-one deriv-
atives from simple and readily available starting materials.
Herein, we wish to report this facile synthetic method for
the preparation of 2-aminobenzofuran-3(2H)-one deriva-
tives starting from 2-azido-1-(2-hydroxyphenyl)ethanones
and terminal alkynoates in the presence of DMAP under
mild reaction conditions.
Introduction
Oxygen-containing heterocycles are of great importance
in the pharmaceutical industry, as they exhibit favorable
biological activity and pharmaceutical significance. The
benzofuran-3(2H)-one moiety constitutes the key structure
of a wide range of compounds that have been used as anti-
fungal agents, tyrosinase inhibitors, antioxidants, an so
on.[1] Moreover, they have been also used as valuable syn-
thetic intermediates to build many functionalized mole-
cules.[2] In recent years, a reaction based on nucleophilic
catalysis through conjugate addition of N and P nucleo-
philes has proven to be useful in the development of cyclo-
addition reactions, providing various carbocycles[3] and het-
erocycles.[4,5] For example, Shi and Alemán et al. described
the reaction of activated allenes or alkynes with salicylald-
imines catalyzed by an organic base to produce oxygen-con-
taining heterocycles (Scheme 1).[6]
Scheme 1. Cyclization reaction of an allenic ester with salicyl N-
tosylimines.[6]
Organic-base-catalyzed cycloaddition reactions with the
use of electron-deficient alkynes has received much atten-
tion.[7] Recently, Xue reported the PPh3-catalyzed cycload-
Scheme 2. Cycloaddition reaction of 1-(o-hydroxyaryl)-3-alkyl-1,3-
diketones with ethyl propiolates.[8]
[a] Department of Chemistry, Huaibei Normal University,
Huaibei, Anhui 235000, P. R. China
Results and Discussion
Fax: +86-0561-3090518
E-mail: leiwang@chnu.edu.cn
Our studies were initiated by the addition of 4-dimethyl-
aminopyridine (DMAP, 20 mol-%) to a solution of 2-azido-
1-(2-hydroxyphenyl)ethanone (1a) and ethyl propiolate (2a)
under various reaction conditions, and the results are
shown in Table 1. The reaction of 1a with 2a in the presence
[b] State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences,
Shanghai 200032, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100250.
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L.-G. Meng, N.-L. Ge, M.-M. Yang, L. Wang
SHORT COMMUNICATION
of DMAP (20 mol-%) in CH2Cl2 at room temperature for with ethyl propiolate (2a) afforded corresponding products
2 h afforded 3a as a pale yellow oil in 55% yield, and this 3 in moderate yields regardless of the different substitutions
1
compound was characterized by H and 13C NMR spec- on the aromatic ring of 1. Clearly, substrates with an elec-
troscopy and HRMS analysis. The ratio of 1a to 2a had an tron-donating group on the benzene ring gave better yields
effect on the yield of the reaction. Desired product 3a was than those with an electron-withdrawing group on the ben-
obtained in 63% yield when 1.5 equiv. of 2a was used, but zene ring. For example, for substrates with a methyl or
the yield did not improved with a further increase in the methoxy group attached on the benzene ring, the yields of
amount of 2a (Table 1, Entries 3 and 4). The yield of 3a the corresponding products were obtained in the range of
could not be improved by heating CH2Cl2 at reflux, but it 64–67% (Table 2, Entries 2–4). Substrates with a chloride
decreased sharply when the reaction was carried out at 0 °C group on the benzene ring gave the desired products in low
(Table 1, Entries 5 and 6). DMAP as a catalyst was crucial yields even when the reaction was prolonged for 12 h
for the reaction. Other organic bases in place of DMAP (Table 2, Entry 5) and most of the starting materials could
were examined and had a significant influence on the reac- not be converted into the desired product. Treatment of 1f
tion. The use of 1,4-diazabicylco[2,2,2]octane (DABCO) af- with ethyl propiolate gave desired product 3f in 61% yield.
forded 3a in 28% yield. Only a trace amount of the desired Notably, multisubstituted 1g could be treated with 2a to
product was detected by TLC when triethylamine (Et3N) or generate desired product 3g in good yield (Table 2, Entry 8).
pyridine was used as catalyst. With the utilization of PPh3 In many cases, the moderate yields obtained in the reactions
or tri(n-butyl)phosphane, desired product 3a was not found. can be accounted for by the formation of other byproducts,
Solvent screening revealed a significant solvent effect. When which could not be isolated by column chromatography.
shifting the solvent to THF, toluene, or acetone, 3a was
obtained in 60, 53 or 31% yield, respectively (Table 1, En-
tries 7–9). With use of DMF or DMSO as a solvent, prod-
Table 2. DMAP-catalyzed cyclization reactions of 2-azido-1-(2-
uct 3a was isolated in a relatively low yield (Table 1, En-
hydroxyphenyl)ethanones with ethyl propiolate.[a]
tries 10 and 11).
Table 1. Effect of substrate ratio and solvent on the reaction.[a]
Entry
1a [equiv.]
2a [equiv.]
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2/3
1.5
2.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
toluene
acetone
DMF
DMSO
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
55
46
63
64
16[c]
62[d]
60
53
31
Ͻ10
Ͻ10
28[e]
trace[f]
trace[g]
[h]
–
[i]
–
[a] Reaction conditions: 1a (0.30 mmol), 2a (amount indicated in
Table 1), DMAP (0.06 mmol), solvent (2.0 mL), r.t., in air, 2 h.
[b] Isolated yield. [c] At 0 °C. [d] CH2Cl2 heated at reflux.
[e] DABCO was used as catalyst. [f] Et3N was used as catalyst.
[g] Pyridine was used as catalyst. [h] PPh3 was used as catalyst.
[i] Tri(n-butyl)phosphane was used as catalyst.
With the reaction conditions optimized for the formation
of 3a in our hand, the scope and limitations of this reaction
were subsequently investigated. A variety of 2-azido-1-(2-
hydroxyphenyl)ethanones 1 were subjected to the reaction
under the optimized conditions, and the representative re-
[a] Reaction conditions: 1 (0.30 mmol), 2a (0.45 mmol), DMAP
(0.06 mmol), CH2Cl2 (2.0 mL), r.t., in air, 2 h. [b] Isolated yield.
sults are listed in Table 2. It was found that reaction of 1 [c] The reaction was stirred for 12 h.
3404 Eur. J. Org. Chem. 2011, 3403–3406
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Synthesis of 2-Aminobenzofuran-3(2H)-one Derivatives
To further evaluate the scope of this reaction, a variety in place of ethyl propiolate, also reacted smoothly with 1a
of electron-deficient alkynes were examined under the stan- to give the desired 2-aminobenzofuran-3(2H)-one deriva-
dard reaction conditions, and the results are summarized in tives in moderate to good yields (Table 3, Entries 3–8). Only
Table 3. Desired product 3h was obtained in 60% yield a trace amount of the desired product was detected by TLC
when methyl propiolate was used as one of the substrates when but-3-yn-2-one was used as the substrate, but the pure
(Table 3, Entry 2). As expected, benzyl or phenyl propiolate, product could not be isolated by column chromatography
Table 3. DMAP-catalyzed cyclization reactions of electron-deficient alkynes with 2-azido-1-(2-hydroxyphenyl)ethanone.[a]
[a] Reaction conditions: 1a (0.30 mmol), 2 (0.45 mmol), DMAP (0.06 mmol), CH2Cl2 (2.0 mL), r.t., in air, 2 h. [b] Isolated yield.
Scheme 3. Plausible mechanism.
Eur. J. Org. Chem. 2011, 3403–3406
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L.-G. Meng, N.-L. Ge, M.-M. Yang, L. Wang
SHORT COMMUNICATION
ject of Science and Technology of the Department of Education,
Anhui Province (No. KJ2011B145).
on silica gel. However, dimethyl acetylenedicarboxylate
failed to gave the corresponding product under the same
reaction conditions.
On the basis of these experiments and previous investi-
gations,[8,9] a mechanistic pathway for this unexpected
DMAP-catalyzed cyclization reaction of 2-azido-1-(2-
hydroxyphenyl)ethanones with terminal alkynoates was
proposed (Scheme 3). The reaction could be triggered by
the nucleophilic addition of DMAP to the electron-
deficient carbon–carbon triple bond of 2a to produce zwit-
terion 4, which can then deprotonate 2-azido-1-(2-hy-
droxyphenyl)ethanone to generate intermediate 5 and 6. In-
termediate 6 could give enolate 7 through a proton-transfer
step. Enolate 7 then undergoes Michael addition to 5 to
give 8 with subsequent generation of 9 through another
proton-transfer step. Intermediate 9 loses N2 to be trans-
formed into 10,[10] which then affords 11 through yet an-
other proton-transfer step. Intermediate 11 might then un-
dergo intramolecular nucleophilic addition to form inter-
mediate 12, followed by proton transfer and elimination of
DMAP to produce desired product 3a.
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Conclusions
In summary, we have developed an unexpected cycliza-
tion reaction of 2-azido-1-(2-hydroxyphenyl)ethanones with
terminal alkynoates in the presence of a catalytic amount
of 4-dimethylaminopyridine (DMAP, 20 mol-%). With the
application of this synthetic method, a series of 2-amino-
benzofuran-3(2H)-one derivatives were prepared in moder-
ate yields under mild reaction conditions. A detailed investi-
gation of the mechanism and the application of this reac-
tion are currently in progress in our laboratory.
Experimental Section
General Procedure for the DMAP-Catalyzed Cyclization of 2-Azido-
1-(2-hydroxyphenyl)ethanones with Terminal Alkynoates: To a solu-
tion of 2-azido-1-(2-hydroxyphenyl)ethanone (0.30 mmol) and the
terminal alkynoate (0.45 mmol, 1.5 equiv.) in dry CH2Cl2 (2.0 mL)
was added DMAP (0.06 mmol). The mixture was then stirred at
room temperature for 2 h. Then, the solvent was removed in vacuo,
and the residue was purified by column chromatography on silica
gel (petroleum ether/EtOAc, 5:1) to give desired 2-aminobenzofur-
an-3(2H)-one product 3.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures, characterization data, and
NMR spectra of all compounds.
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Acknowledgments
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (No. 20972057) and the Pro-
Received: February 23, 2011
Published Online: May 17, 2011
3406
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3403–3406