Metal-free oxidative cyclization of o-acylphenols for the construction of 2-aminobenzofuran-3(2H)-ones

Article abstract of DOI:10.1002/ejoc.201301756

An efficient metal-free approach to the synthesis of 2-aminobenzofuran- 3(2H)-ones has been developed. Using TBHP as an oxidant and I₂ (or TBAI) as catalyst, 2-acylphenols were treated with secondary amines to provide 2-aminobenzofuran-3(2H)-one derivatives in moderate to good yields. A possible reaction pathway for the formation of 2-dimorpholinobenzofuran-3(2H)-one is also discussed herein. Copyright

Full text of DOI:10.1002/ejoc.201301756

FULL PAPER
DOI: 10.1002/ejoc.201301756
Metal-Free Oxidative Cyclization of o-Acylphenols for the Construction of
2-Aminobenzofuran-3(2H)-ones
Hui Yu,*[a] Weihua Huang,[a] and Fengling Zhang[a]
Keywords: Synthetic methods / Cyclization / Oxygen heterocycles / Amines
An efficient metal-free approach to the synthesis of 2-amino-
benzofuran-3(2H)-ones has been developed. Using TBHP as
an oxidant and I2 (or TBAI) as catalyst, 2-acylphenols were
treated with secondary amines to provide 2-aminobenzo-
furan-3(2H)-one derivatives in moderate to good yields. A
possible reaction pathway for the formation of 2-dimorphol-
inobenzofuran-3(2H)-one is also discussed herein.
and quinazolines.[5i,5j] Here we extend the application of
this protocol and report on the oxidative cyclization of o-
acylphenols for the synthesis of 2-aminobenzofuranones
using this metal-free oxidative system.[6]
Introduction
Benzofuran-3(2H)-ones (coumaranones) have received
much attention in the medicinal and pharmaceutical fields
because of their broad pharmacological activities including
in vitro antibacterial, anticancer, antifeedant and anti-
parasitic activities.[1] They are also important intermediates Results and Discussion
in the synthesis of various bioactive compounds such as
Initially, the reaction of 2-acetylphenol 1a with 2.0 equiv.
heliquinomycin analogues,[2a] BKCa channel openers,[2b]
and 5-HT1A receptors.[2c] Various synthetic routes have
been developed for the synthesis of the benzofuran-3(2H)-
one framework but most of these methods require multiple
steps or aggressive conditions.[3] Thus, a convenient method
for the preparation of the benzofuran-3(2H)-one frame-
work would be of benefit. Oxidative cyclization of o-acyl
phenols is a simple pathway for the synthesis of benzo-
furan-3(2H)-one derivatives.[4] However, excess PhI(OAc)2
must be used as the oxidative reagent for this transforma-
tion and 2 equiv. of PhI are generated as the main by-prod-
uct. Therefore, an alternative oxidant for the cyclization
process is essential. Because of its high efficiency and envi-
ronmentally friendly properties, the TBHP/I2 system has
emerged in recent years as an attractive metal-free oxidative
method and has been used successfully for the formation
of carbon–carbon and carbon–heteroatom bonds.[5a–5k] In
most cases, these reactions were carried out under mild con-
ditions and only small molecules such as H2O and tBuOH
were released as the main by-products. In this new method,
synthetically or pharmaceutically useful compounds were
prepared in excellent yields. This was the case for imides,[5b]
α-ketonamides,[5c,5d] nitriles,[5e] pyridines,[5f] oxazoles,[5g,5h]
of morpholine 2a was examined in CH3CN with I2 (15 mol-
%) as catalyst, and aqueous TBHP (3.0 equiv.) as the oxi-
dant at room temperature. A product identified as 2,2-di-
Table 1. Screening conditions (DTBP = di-tert-butyl peroxide; CHP
= cumene hydroperoxide).[a]
Entry Catalyst
(mol-%)
Oxidant
Solvent
Yield
[%][b]
1
2
3
4
5
6
7
8
I2 (15)
NH4I (30)
KI (30)
NIS (30)
TBAI (30)
I2 (15)
I2 (15)
I2 (15)
I2 (15)
I2 (15)
I2 (15)
I2 (15)
–
aq. TBHP
aq. TBHP
aq. TBHP
aq. TBHP
aq. TBHP
aq. TBHP
aq. TBHP
O2
H2O2
DTBP
CHP
–
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
EtOAc
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
80
31
22
76
72
71
59
Ͻ10
Ͻ10
15
9
10
11
12
13
14[c]
24
Ͻ10
Ͻ10
52
aq. TBHP
aq. TBHP
[a] Department of Chemistry, Tongji University,
Siping Road 1239, 200092 Shanghai, China
E-mail: yuhui@tongji.edu.cn
I2 (15)
[a] Reaction conditions: 2-acetylphenol (0.5 mmol), morpholine
(1.5 mmol), in CH3CN (2.0 mL) at room temperature for 16 h. [b]
Isolated yield. [c] TsOH (50 mol-%) as additive.
http://chemweb.tongji.edu.cn/Teachers/Organic
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301756
3156
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Eur. J. Org. Chem. 2014, 3156–3162

Metal-Free Construction of 2-Aminobenzofuran-3(2H)-ones
morpholinobenzofuran-3(2H)-one 3a was isolated in 55% tion, 5 was also formed (as detected by LCMS) in the mix-
yield 24 h later.[9] The yield of 3a could be improved to 80% ture solution of 1a and 15 mol-% I2 in CH3CN after stirring
when the amount of morpholine and TBHP was increased for 4 h at room temperature. Subsequent addition of TBHP
to 3.0 equiv. and 4.0 equiv., respectively, and the reaction and 3.0 equiv. morpholine 2a to the resultant solution gave
time decreased to 16 h (Table 1, Entry 1). Other iodine 3a in 68% yield (Scheme 1, d). We hypothesize that benzo-
source reagents (30 mol-%) were also screened under the furan-3(2H)-one 5 may be the key intermediate in the reac-
same conditions. The results show that the use of NH4I or tion; 5 was generated from 1a by an iodination/cyclization
KI correlated to lower yields whereas the use of NIS[7] and process. Compound 5 was then converted to 3a through
TBAI[8] enabled moderate yields of 3a to be achieved a duplicate iodination/C–N bond formation process with
(Table 1, Entries 2–5). The use of EtOAc or toluene as sol- compound 6 as the intermediate (as detected by LCMS)
vents resulted in the formation of 3a with lower yields (Scheme 2). Full elucidation of all mechanistic details re-
(Table 1, Entries 6, 7). Other commercial oxidants such as quires further investigation.
O2, H2O2, DTBP, and CHP were also tested although yields
of only 10–24% for 3a were obtained in these cases (Table 1,
Entries 8–11). In the absence of I2 or TBHP, no separable
amount of product was observed (Table 1, Entries 12, 13).
TsOH was used to promote the reaction but its use led to
a low yield (Table 1, Entry 14). On the basis of these results
the conditions described by (Table 1, Entry 1) are clearly
optimal for the given transformation.
To gain insight into the reaction mechanism, control ex-
periments were carried out with results shown in Scheme 1.
The reaction proceeded well in the presence of 1.0 equiv.
Scheme 2. Possible reaction pathway.
TEMPO, so
a radical pathway could be excluded
(Scheme 1, a). An unusual intermediate compound 4 was
prepared and subjected to the reaction conditions;[10] un-
Once the optimized reaction conditions had been estab-
identifiable compounds were produced and only traces of lished, the substrate scope was examined; results of these
product 3a were found. These results suggest that the inter- studies are summarized in Table 2. Different 2-acetylphen-
molecular C–N bond formation may not occur prior to in- ols with electron-donating or electron-withdrawing groups
tramolecular C–O bond formation (Scheme 1, b). The cou- on the benzene ring reacted smoothly with morpholine 2a
pling of benzofuran-3(2H)-one 5 and 3.0 equiv. morpholine to give corresponding benzofuran-3(2H)-ones in moderate
was then tested under standard conditions, and desired to good yields (Table 2, compounds 3b–3f). Multi-substi-
product 3a was obtained in 55% yield (Scheme 1, c). The tuted benzofuran-3(2H)-one 3g could also be prepared un-
low yield of 3a could be explained by the high reactivity of der standard conditions in moderate yield (Table 2, 3g). A
5 under oxidative conditions. In a two-step one-pot reac- heterocyclic substrate such as 1-acetyl-2-hydroxynaphthal-
Scheme 1. Control experiments.
Eur. J. Org. Chem. 2014, 3156–3162
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H. Yu, W. Huang, F. Zhang
FULL PAPER
Table 2. TBHP/I2-promoted synthesis of 2-aminobenzofuran-3(2H)-ones.[a,b]
[a] On 0.3 mmol scale. [b] Isolated yield.
ene reacted with morpholine 2a to form the corresponding methyl-2-morpholinobenzofuran-3(2H)-one 7a was ob-
product in 64% yield (Table 2, 3i). Next, a variety of amines tained as the major product in 52% yield. Further investiga-
was employed to react with 2-acetylphenol 1a. Piperidine tion showed that the yield of 7a could be increased to 85%
and pyrrolidine reacted with 1a to give the corresponding when TBAI was used as catalyst instead of I2. The scope of
products in 72% and 52% yield, respectively (Table 2, 3j, the coupling reaction of different o-acylphenols with
3k). Substituted piperazines were also suitable substrates to amines was examined under optimized conditions. As
produce the corresponding products in suitable yields shown in Table 3, 2-propionylphenols with electron-donat-
(Table 2, 3l–3p). When an acyclic secondary amine such as ing or electron-withdrawing groups on the phenyl ring gave
N-methylbenzylamine was used, the desired product could products in excellent yields (Table 3, 7b–7d). For example,
not be isolated from the reaction mixture as it readily de- the reaction of 4-methyl- or 4-fluoro-2-propionylphenol
composed during the concentration and purification pro- with morpholine gave the corresponding products 7b and
cess. For primary amines such as benzylamine, no reaction 7d in 83% and 79% yield, respectively. Other cyclic amines
occurred and all starting materials remained untouched such as piperidine and substituted piperizines reacted with
(Table 2, 3q, 3r). Finally, diamines such as N,NЈ-dimethyl- 2-propionylphenol to give products in good yields (Table 3,
ethylenediamine and N,NЈ-dimethyl-1,3-propanediamine 7e–7h). Acyclic secondary or primary amines were not suit-
were treated with 1a to prepare cyclic compounds, but no able as reaction substrates and formed complex mixtures
desired products were found.
(Table 3, 7i, 7j). Additionally, o-butyrylphenol and o-phen-
The reactivity of 2-propionylphenol with morpholine 2a ylacetylphenol were found to react with morpholine afford-
under optimized conditions was also examined, and 2- ing desired products in moderate yields (Table 3, 7k–7m).
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Metal-Free Construction of 2-Aminobenzofuran-3(2H)-ones
Table 3. TBHP/TBAI-promoted synthesis of 2-aminobenzofuran-3(2H)-ones.[a,b]
[a] On a 0.5 mmol scale. [b] Isolated yield.
ished, the mixture was quenched with saturated sodium thiosulfate
Conclusions
solution, then extracted with EtOAc, dried with anhydrous
Na2SO4, and evaporated in vacuo. The residue was purified by
flash column chromatography on silica gel (PE/EtOAc, 8:1) to give
product 3a.
We have developed a practical metal-free method for the
synthesis of 2-aminobenzofuran-3(2H)-ones by the oxidat-
ive coupling of o-acylphenols and amines. The reaction is
carried out under mild conditions using TBHP as the oxi-
dant and I2 (or TBAI) as catalyst. Methods for converting
the obtained 2-aminobenzofuran-3(2H)-ones to other
benzofuran-3(2H)-one derivatives are currently being devel-
oped in our laboratory.
2,2-Dimorpholinobenzofuran-3(2H)-one (3a): Yellow solid; Rf = 0.55
(PE/AcOEt = 4:1); 126 mg (83% yield); m.p. 156.6–159.9 °C; 1H
NMR (400 MHz, CDCl3): δ = 7.71–7.53 (m, 2 H), 7.05 (t, J =
7.2 Hz, 2 H), 3.67 (t, J = 4.6 Hz, 8 H), 3.01–2.84 (m, 4 H), 2.76–
2.59 (m, 4 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 198.1, 170.6,
139.3, 123.8, 121.8, 121.3, 112.6, 109.5, 66.9, 45.7 ppm. HRMS
(ESI) m/z [M + H]+ calcd. for C16H21N2O4 305.1501, found
305.1517.
Experimental Section
5-Methyl-2,2-dimorpholinobenzofuran-3(2H)-one (3b): Yellow solid;
Rf = 0.50 (PE/AcOEt = 4:1); Rf = 0.50 (PE/AcOEt = 4:1); 119 mg
(75% yield); m.p. 107.6–109.8 °C; H NMR (400 MHz, CDCl3): δ
= 7.51–7.40 (m, 1 H), 7.36 (s, 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 3.67
(t, J = 4.6 Hz, 8 H), 2.99–2.81 (m, 4 H), 2.75–2.56 (m, 4 H), 2.33
(s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 198.1, 168.9,
140.5, 131.5, 123.2, 121.1, 112.2, 109.5, 66.9, 45.6, 20.6 ppm.
HRMS (ESI) m/z [M + H]+ calcd. for C17H23N2O4 319.1658, found
319.1666.
General Methods: Commercially available reagents were used as re-
ceived without further purification unless otherwise indicated. Re-
actions were magnetically stirred and monitored by thin layer
chromatography (TLC) using Silica Gel 60 F254 plates and were
visualized by fluorescence quenching at 254 nm. For chromato-
graphic purifications, analytically pure solvents were used and the
silica gel 300–400 mesh was used as the solid support. 1H NMR
and 13C NMR chemical shifts are reported in δ units, parts per
million (ppm) relative to the chemical shift of residual protonated
solvent. Reference peaks for chloroform in 1H NMR and 13C
NMR spectra were set at δ = 7.26 ppm and 77.0 ppm, respectively.
1
5-Ethoxy-2,2-dimorpholinobenzofuran-3(2H)-one (3c): Yellow solid;
Rf = 0.50 (PE/AcOEt = 4:1); 118 mg (68% yield); m.p. 117.6–
119.2 °C; 1H NMR (400 MHz, CDCl3): δ = 7.29–7.24 (m, 1 H),
Typical Experimental Procedure for the Synthesis of 2-Aminobenzo-
furan-3(2H)-ones 3a–3p: In a 15 mL reaction tube, a mixture of 2- 6.97 (dd, J = 8.5, 5.9 Hz, 2 H), 3.99 (q, J = 7.0 Hz, 2 H), 3.73–3.57
acetylphenol (68 mg, 0.5 mmol), morpholine (132 mg, 1.5 mmol),
tert-butyl hydroperoxide (70% in H2O, 2 mmol), and I2
(19 mg,0.075 mmol) in acetonitrile (2.0 mL) was stirred at room
temperature under air for 16 h, until complete consumption of
starting material as monitored by TLC. After the reaction was fin-
(m, 8 H), 2.99–2.83 (m, 4 H), 2.76–2.55 (m, 4 H), 1.41 (t, J =
7.0 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 198.4, 165.7,
154.1, 129.5, 120.9, 113.5, 109.9, 104.4, 66.9, 64.2, 45.6, 14.7 ppm.
HRMS (ESI) m/z [M + H]+ calcd. for C18H25N2O5 349.1763, found
349.1755.
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H. Yu, W. Huang, F. Zhang
FULL PAPER
4-Fluoro-2,2-dimorpholinobenzofuran-3(2H)-one (3d): Yellow solid;
Rf = 0.55 (PE/AcOEt = 4:1); 112 mg (70% yield); m.p. 183.8–
186.5 °C; 1H NMR (400 MHz, CDCl3): δ = 7.60 (dd, J = 8.4,
2,2-Di(pyrrolidin-1-yl)benzofuran-3(2H)-one (3k): Yellow oil; Rf =
0.30 (DCM/MeOH = 8:1); 84 mg (62% yield); 1H NMR (400 MHz,
CDCl3): δ = 7.57 (dd, J = 8.3, 1.7 Hz, 1 H), 7.23 (ddd, J = 8.7,
6.0 Hz, 1 H), 6.97–6.23 (m, 2 H), 3.94–3.42 (m, 8 H), 2.99–2.73 (m, 6.5, 1.9 Hz, 1 H), 6.54 (d, J = 8.9 Hz, 1 H), 6.32–6.19 (m, 1 H),
4 H), 2.82–2.51 (m, 4 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 3.84–3.69 (m, 4 H), 3.70–3.59 (m, 4 H), 1.95 (t, J = 8.2 Hz,
195.8, 172.1, 171.9, 168.9, 126.1, 126.2, 111.2, 110.6, 110.4, 100.2,
8 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 182.1, 178.7, 165.4,
99.9, 66.8, 45.7 ppm. HRMS (ESI) m/z [M + H]+ calcd. for 138.2, 128.9, 125.6, 119.5, 112.3, 77.3, 77.2, 77.0, 76.7, 50.9, 29.7,
C16H20FN2O4 323.1407, found 323.1424.
25.1 ppm. HRMS (ESI) m/z [M + H]+ calcd. for C16H21N2O2
273.1603, found 273.1608.
5-Fluoro-2,2-dimorpholinobenzofuran-3(2H)-one (3e): Yellow solid;
Rf = 0.55 (PE/AcOEt = 4:1); 120 mg (75% yield); m.p. 153.5–
2,2-Bis(4-methylpiperazin-1-yl)benzofuran-3(2H)-one (3l): Yellow
156.2 °C; 1H NMR (400 MHz, CDCl3): δ = 7.38 (dt, J = 8.8, solid; Rf = 0.35 (PE/AcOEt = 4:1); 123 mg (75% yield); m.p. 196.5–
2.8 Hz, 1 H), 7.23 (dd, J = 6.5, 2.8 Hz, 1 H), 7.04 (dd, J = 9.0,
3.6 Hz, 1 H), 3.67 (t, J = 4.6 Hz, 8 H), 2.98–2.82 (m, 4 H), 2.72–
2.58 (m, 4 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 197.8 (d,
199.3 °C; 1H NMR (400 MHz, CDCl3): δ = 7.66–7.50 (m, 2 H),
7.13–6.88 (m, 2 H), 2.96–2.84 (m, 4 H), 2.75–2.62 (m, 4 H), 2.52–
2.30 (m, 8 H), 2.27 (s, 6 H) ppm. 13C NMR (101 MHz, CDCl3): δ
= 198.3, 170.4, 139.1, 123.7, 121.5, 121.3, 112.5, 110.0, 55.0, 45.9,
44.9 ppm. HRMS (ESI) m/z [M + H]+ calcd. for C18H27N4O2
331.2134, found 331.2127.
JC,F = 2.7 Hz), 166.7, 157.5 (d, JC,F = 243.8 Hz), 126.8 (d, JC,F
=
25.5 Hz), 121.5 (d, JC,F = 7.4 Hz), 113.8 (d, JC,F = 7.4 Hz), 110.7,
108.9 (d, JC,F = 23.5 Hz), 66.8, 45.6 ppm. HRMS (ESI) m/z [M +
H]+ calcd. for C15H12NOS 254.0640, found 254.0653 C16H20FN2O4
323.1407, found 323.1417.
2,2-Bis(4-ethylpiperazin-1-yl)benzofuran-3(2H)-one (3m): Yellow so-
lid; Rf = 0.35 (PE/AcOEt = 4:1); 132 mg (74% yield); m.p. 201.2–
203.5 °C; 1H NMR (400 MHz, CDCl3): δ = 7.57 (dd, J = 12.8,
12.1 Hz, 2 H), 7.14–6.89 (m, 2 H), 2.83–2.66 (m, 4 H), 2.65–2.21
5-Bromo-2,2-dimorpholinobenzofuran-3(2H)-one (3f): Yellow solid;
Rf = 0.55 (PE/AcOEt = 4:1); 137 mg (72% yield); m.p. 155.6–
157.9 °C; 1H NMR (400 MHz, CDCl3): δ = 7.80–7.60 (m, 2 H), (m, 12 H), 1.08 (t, J = 7.2 Hz, 6 H) ppm. 13C NMR (101 MHz,
6.98 (d, J = 8.6 Hz, 1 H), 3.66 (dd, J = 10.5, 6.1 Hz, 8 H), 3.00–2.80
CDCl3): δ = 198.2, 170.4, 139.1, 123.8, 121.6, 121.3, 112.5, 109.8,
(m, 4 H), 2.72–2.53 (m, 4 H) ppm. 13C NMR (101 MHz, CDCl3): δ 52.6, 52.1, 44.7, 11.6 ppm. HRMS (ESI) m/z [M + H]+ calcd. for
= 196.8, 169.1, 141.8, 126.3, 122.7, 114.5, 114.3, 110.6, 66.8, 45.6,
29.6 ppm. HRMS (ESI) m/z [M + H]+ calcd. for C16H20BrN2O4
383.0606, found 383.0622.
C20H31N4O2 35902447, found 359.2423.
2,2-Bis(4-phenylpiperazin-1-yl)benzofuran-3(2H)-one (3n): Yellow
solid; Rf = 0.38 (PE/AcOEt = 4:1); 154 mg (yield 68%); m.p. 115.6–
1
5-Iodo-2,2-dimorpholinobenzofuran-3(2H)-one (3g): Yellow solid; Rf
117.8 °C; H NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 7.1 Hz, 2
= 0.53 (PE/AcOEt = 4:1); 139 mg (65% yield); m.p. 156.7–
158.8 °C; H NMR (400 MHz, CDCl3): δ = 7.89 (s, 2 H), 6.88 (d,
H), 7.25 (t, J = 8.0 Hz, 4 H), 7.07 (d, J = 7.9 Hz, 2 H), 6.88 (dd,
J = 13.4, 7.7 Hz, 6 H), 3.31–3.05 (m, 12 H), 2.88 (d, J = 5.6 Hz, 4
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 198.3, 170.5, 151.2,
1
J = 9.2 Hz, 1 H), 3.66 (t, J = 4.5 Hz, 8 H), 2.99–2.82 (m, 4 H),
2.71–2.53 (m, 4 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 196.4, 139.3, 129.1,123.8, 121.8, 121.3, 119.8, 116.1, 112.6, 109.8, 49.3,
169.7, 147.3, 132.5, 123.4, 114.9, 110.4, 83.7, 66.7, 45.7 ppm.
HRMS (ESI) m/z [M + H]+ calcd. for C16H20IN2O4 431.0468,
found 431.0484.
45.2 ppm. HRMS (ESI) m/z [M + H]+ calcd. for C28H31N4O2
455.2447, found 455.2427.
2,2-Bis(4-ethoxylcarbonylpiperazin-1-yl)benzofuran-3(2H)-one (3o):
Yellow solid; Rf = 0.30 (PE/AcOEt = 4:1); 156 mg (yield 70%);
6-Methoxy-2,2-dimorpholino-5-nitrobenzofuran-3(2H)-one (3h): Yel-
low solid; Rf = 0.40 (PE/AcOEt = 4:1); 98 mg (52% yield); m.p.
1
m.p. 191.3–194.1 °C; H NMR (400 MHz, CDCl3): δ = 7.64 (d, J
183.8–186.5 °C; 1H NMR (400 MHz, CDCl3): δ = 8.30 (s, 1 H), = 8.1 Hz, 1 H), 7.57 (d, J = 7.6 Hz, 1 H), 7.05 (t, J = 8.1 Hz, 2 H),
6.44 (s, 1 H), 4.01 (s, 3 H), 3.78–3.60 (m, 8 H), 3.12–3.00 (m, 4 H), 4.11 (q, J = 7.1 Hz, 4 H), 3.46 (s, 8 H), 2.88 (d, J = 3.7 Hz, 4
2.95 (ddd, J = 9.6, 5.8, 3.2 Hz, 4 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 190.5, 175.3, 162.3, 134.1, 125.7, 114.1, 98.7, 66.6,
H), 2.76–2.35 (m, 4 H), 1.23 (t, J = 7.1 Hz, 6 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 197.9, 170.3, 155.2, 139.4, 123.8, 121.9,
57.2, 47.3, 46.1 ppm. HRMS (ESI) m/z [M + H]+ calcd. for 121.1, 112.6, 109.4, 61.3, 45.1, 43.7, 29.7, 14.6 ppm. HRMS (ESI)
C17H22N3O7 380.1458, found 380.1443.
2,2-Dimorpholinonaphtho[2,1-b]furan-1(2H)-one (3i): Yellow solid; 2,2-Bis(4-tert-butylcarbonylpiperazin-1-yl)benzofuran-3(2H)-one
Rf = 0.50 (PE/AcOEt = 4:1); 113 mg (64% yield); m.p. 116.4– (3p): Yellow solid; Rf = 0.30 (PE/AcOEt = 4:1); 168 mg (yield
117.8 °C; H NMR (400 MHz, CDCl3): δ = 8.71 (d, J = 8.2 Hz, 1 67%); m.p. 199.8–201.8 °C; 1H NMR (400 MHz, CDCl3): δ = 7.74–
H), 8.13 (d, J = 9.0 Hz, 1 H), 7.82 (d, J = 8.1 Hz, 1 H), 7.67 (s, 1 7.40 (m, 2 H), 7.06 (dd, J = 23.8, 17.1 Hz, 2 H), 3.62–3.22 (m, 8
H), 7.47 (s, 1 H), 7.21 (d, J = 9.0 Hz, 1 H), 3.69 (t, J = 4.6 Hz, 8 H), 2.86 (d, J = 5.1 Hz, 4 H), 2.76–2.44 (m, 4 H), 1.43 (s, 18
m/z [M + H]+ calcd. for C22H31N4O6 447.2244, found 447.2226.
1
H), 3.10–2.87 (m, 4 H), 2.77 (dd, J = 10.7, 5.6 Hz, 4 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 197.4, 173.3, 141.3, 130.2, 129.0,
128.6, 128.5, 125.4, 123.0, 113.2, 113.1, 110.5, 77.3, 76.7, 66.9,
45.7 ppm. HRMS (ESI) m/z [M + H]+ calcd. for C20H23N2O4
355.1658, found 355.1648.
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 198.0, 170.3, 154.4,
139.3, 123.8, 121.9, 121.1, 112.6, 109.6, 79.6, 45.1, 28.3 ppm.
HRMS (ESI) m/z [M + H]+ calcd. for C26H39N4O6 503.2870, found
503.2850.
Typical Experimental Procedure for the Synthesis of 2-Aminobenzo-
furan-3(2H)-one 7a–7h, 7k–7m: In a 15 mL reaction tube, a mixture
of 2-propionylphenol (75 mg, 0.5 mmol), morpholine (66 mg,
2,2-Di(piperidin-1-yl)benzofuran-3(2H)-one (3j): Yellow solid; Rf =
0.40 (DCM/MeOH = 8:1); 108 mg (72% yield); m.p. 140.9–
143.1 °C. 1H NMR (400 MHz, CDCl3): δ = 7.65–7.51 (m, 2 H), 0.75 mmol), tert-butyl hydroperoxide(70% in H2O, 2 mmol), and
7.02 (t, J = 7.0 Hz, 2 H), 2.95–2.84 (m, 4 H), 2.72–2.65 (m, 4 H),
2.51–2.30 (m, 8 H), 2.26–2.18 (m, 4 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 198.1, 170.6, 139.3, 123.8, 121.8, 121.3, 112.6, 109.5,
66.9, 45.7 ppm. HRMS (ESI) m/z [M + H]+ calcd. for C18H25N2O2
301.1916, found 301.1887.
TBAI (55 mg, 0.15 mol) in acetonitrile (2.0 mL) was stirred at room
temperature under air for 16 h, until complete consumption of
starting material as monitored by TLC. After the reaction was fin-
ished, the mixture was quenched with saturated sodium thiosulfate
solution, then extracted with EtOAc, dried over anhydrous
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Eur. J. Org. Chem. 2014, 3156–3162

Metal-Free Construction of 2-Aminobenzofuran-3(2H)-ones
Na2SO4, and the solvents evaporated under vacuum. The residue
was purified by flash column chromatography over silica gel (PE/
EtOAc, 8:1) to give product 7a.
43.4, 19.9, 14.6 ppm. HRMS (ESI) m/z [M + H]+ calcd. for
C16H21N2O4 305.1501, found 305.1491.
2-(4-tert-Butylcarbonylpiperazin-1-yl)-2-methylbenzofuran-3(2H)-
one (7h): Yellow oil; Rf = 0.47 (PE/AcOEt = 4:1); 103 mg (62%
yield) 1H NMR (400 MHz, CDCl3): δ = 7.68 (d, J = 27.4 Hz, 2 H),
7.22–6.94 (m, 2 H), 3.50 (s, 4 H), 2.87 (d, J = 21.0 Hz, 2 H), 2.62
(d, J = 23.3 Hz, 2 H), 1.53 (dd, J = 51.2, 34.9 Hz, 12 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 200.6, 170.9, 154.2, 138.7, 124.7,
121.1, 119.4, 113.5, 102.0, 79.7, 45.6, 28.3, 19.9 ppm. HRMS (ESI)
m/z [M + H]+ calcd. for C18H25N2O4 333.1814, found 333.1801.
2-Methyl-2-morpholinobenzofuran-3(2H)-one (7a): Yellow oil; Rf =
0.53 (PE/AcOEt = 4:1); 99 mg (85% yield) 1H NMR (400 MHz,
CDCl3): δ = 7.66 (t, J = 7.5 Hz, 2 H), 7.06 (dd, J = 12.3, 4.9 Hz,
2 H), 3.73 (m, J = 11.2, 10.4, 7.1 Hz, 4 H), 2.96–2.79 (m, 2 H),
2.74–2.56 (m, 2 H), 1.56 (s, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 200.5, 171.0, 138.8, 124.8, 121.4, 119.8, 113.3, 102.4,
66.6, 45.8, 19.5 ppm. HRMS (ESI) m/z [M + Na]+ calcd. for
C13H15NO3Na 256.0952, found 256.0937.
2-Ethyl-2-morpholinobenzofuran-3(2H)-one (7k): Yellow oil; Rf =
0.86 (PE/AcOEt = 4:1); 75 mg(61% yield) 1H NMR (400 MHz,
CDCl3): δ = 7.71–7.59 (m, 2 H), 7.06 (dd, J = 17.0, 8.3 Hz, 2 H),
3.81–3.65 (m, 4 H), 2.90–2.81 (m, 2 H), 2.69–2.61 (m, 2 H), 2.10–
1.98 (m, 2 H), 0.86 (d, J = 7.5 Hz, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 200.3, 171.4, 138.7, 124.0, 121.3, 112.9, 105.0, 66.7,
46.1, 26.3, 6.9 ppm. HRMS (ESI) m/z [M + H]+ C14H18NO3
248.1288, found 248.1266.
2,5-Dimethyl-2-morpholinobenzofuran-3(2H)-one (7b): Yellow oil;
Rf = 0.56 (PE/AcOEt = 4:1); 103 mg (83 % yield) 1H NMR
(400 MHz, CDCl3): δ = 7.52–7.42 (m, 2 H), 6.98 (d, J = 8.4 Hz, 1
H), 3.81–3.67 (m, 4 H), 2.91–2.82 (m, 2 H), 2.69–2.60 (m, 2 H),
2.36 (s, 3 H), 1.55 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ
= 200.4, 169.4, 140.3, 131.0, 124.1, 119.7, 112.7, 102.4, 66.5, 45.9,
20.4, 19.5 ppm. HRMS (ESI) m/z [M + Na]+ calcd. for
C14H17NO3Na 270.1106, found 270.1101.
2-Ethyl-5-fluoro-2-morpholinobenzofuran-3(2H)-one (7l): Yellow oil;
Rf = 0.89 (PE/AcOEt = 4:1); 89 mg (67 % yield) 1H NMR
(400 MHz, CDCl3): δ = 7.38 (td, J = 8.8, 2.8 Hz, 1 H), 7.28 (t, J
= 3.2 Hz, 1 H), 7.05 (dd, J = 9.0, 3.6 Hz, 1 H), 3.80–3.66 (m, 4 H),
2.87–2.81 (m, 2 H), 2.67–2.60 (m, 2 H), 2.05 (ddd, J = 29.2, 14.6,
7.3 Hz, 2 H), 0.86 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (101 MHz,
6-Ethoxy-2-methyl-2-morpholinobenzofuran-3(2H)-one (7c): Yellow
oil; Rf = 0.48 (PE/AcOEt = 4:1); 82 mg(61 % yield) 1H NMR
(400 MHz, CDCl3): δ = 7.56 (d, J = 8.6 Hz, 1 H), 6.60 (dd, J =
8.6, 1.8 Hz, 1 H), 6.45 (d, J = 1.7 Hz, 1 H), 4.12 (q, J = 7.0 Hz, 2
H), 3.84–3.65 (m, 4 H), 2.92–2.81 (m, 2 H), 2.73–2.58 (m, 2 H),
1.56 (s, 3 H), 1.47 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 197.8, 173.2, 168.4, 125.9, 112.6, 111.5, 103.3, 96.1,
66.7, 64.2, 45.8, 19.7, 14.5 ppm. HRMS (ESI) m/z [M + Na]+ calcd.
for C15H19NO4Na 300.1212, found 300.1201.
CDCl3): δ = 200.1 (d, JC,F = 3.0 Hz), 167.8, 157.2 (d, JC,F
=
242.8 Hz), 126.5 (d, JC,F = 25.7 Hz), 121.4 (d, JC,F = 7.7 Hz), 114.1
(d, JC,F = 7.5 Hz), 109.2 (d, JC,F = 23.4 Hz), 106.2, 66.7, 46.1, 26.2,
6.8 ppm. HRMS (ESI) m/z [M + H]+ calcd. for C14H17FNO3
266.1192, found 266.1183.
5-Fluoro-2-methyl-2-morpholinobenzofuran-3(2H)-one (7d): Yellow
oil; Rf = 0.61 (PE/AcOEt = 4:1); 98.5 mg(79% yield) 1H NMR
(400 MHz, CDCl3): δ = 7.38 (dd, J = 11.9, 5.6 Hz, 1 H), 7.33–7.27
(m, 1 H), 7.08–7.00 (m, 1 H), 3.73 (ddd, J = 17.0, 14.2, 10.8 Hz, 4
H), 2.94–2.79 (m, 2 H), 2.63 (d, J = 3.9 Hz, 2 H), 1.55 (s, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 200.2 (d, JC,F = 3.0 Hz), 167.2,
157.3 (d, JC,F = 243.0 Hz), 126.7 (d, JC,F = 25.7 Hz), 120.0 (d, JC,F
= 7.8 Hz), 114.5 (d, JC,F = 7.5 Hz), 109.5 (d, JC,F = 23.4 Hz), 103.7,
66.6, 45.9, 19.5 ppm. HRMS (ESI) m/z [M + Na]+ calcd. for
C13H14FNO3Na 252.1036, found 252.1031.
5-Fluoro-2-morpholino-2-phenylbenzofuran-3(2H)-one (7m): Yellow
oil; Rf = 0.79 (PE/AcOEt = 4:1); 80 mg (51 % yield) 1H NMR
(400 MHz, CDCl3): δ = 7.74–7.63 (m, 2 H), 7.43 (td, J = 8.8,
2.8 Hz, 1 H), 7.40–7.32 (m, 3 H), 7.27–7.18 (m, 2 H), 3.79–3.65 (m,
4 H), 2.79–2.65 (m, 4 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
197.3 (d, JC,F = 3.0 Hz), 167.5, 157.6 (d, JC,F = 243.3 Hz), 134.4,
129.1,128.8, 126.7, 126.5 (d, JC,F = 25.7 Hz), 120.0 (d, JC,F
=
7.8 Hz), 114.1 (d, JC,F = 7.5 Hz), 110.1 (d, JC,F = 23.6 Hz), 106.3,
66.9, 46.64 ppm. HRMS (ESI) m/z [M + Na]+ calcd. for
C18H16FNNaO3 336.1012, found 336.1013.
2-Methyl-2-(piperidin-1-yl)benzofuran-3(2H)-one (7e): Yellow oil; Rf
1
= 0.67 (PE/AcOEt = 4:1); 94 mg(81% yield) H NMR (400 MHz,
1-(2-Hydroxylphenyl)-2-morpholinoethane-1,2-dione (8): Rf = 0.53
(PE/AcOEt = 4:1); Yellow solid; 63 mg (54 % yield); 1H NMR
(400 MHz, CDCl3): δ = 11.25 (s, 1 H), 7.56 (t, J = 7.3 Hz, 2 H),
7.06–6.83 (m, 2 H), 3.89–3.73 (m, 5 H), 3.72–3.62 (m, 2 H), 3.47–
3.32 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 197.9, 170.3,
155.2, 139.4, 123.8, 121.9, 121.1, 112.6, 109.4, 61.3, 45.1, 43.6, 29.6,
14.6 ppm.
CDCl3): δ = 7.70–7.59 (m, 2 H), 7.03 (dd, J = 12.1, 4.8 Hz, 2 H),
2.90–2.81 (m, 2 H), 2.65–2.54 (m, 2 H), 1.70–1.57 (m, 4 H), 1.56
(s, 3 H), 1.47 (dd, J = 11.5, 5.7 Hz, 2 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 201.4, 170.9, 138.3, 124.7, 121.2, 119.9, 113.2, 103.7,
46.6, 25.7, 24.2, 20.1 ppm. HRMS (ESI) m/z [M + H]+ calcd. for
C14H18NO2 232.1338, found 232.1305.
2-(4-Ethylpiperazin-1-yl)-2-methylbenzofuran-3(2H)-one (7f): Yel-
low oil; Rf = 0.58 (PE/AcOEt = 4:1); 116 mg (90% yield) 1H NMR
(400 MHz, CDCl3): δ = 7.63 (t, J = 8.2 Hz, 2 H), 7.03 (t, J =
7.5 Hz, 2 H), 3.00 (s, 2 H), 2.77 (s, 2 H), 2.63 (d, J = 20.4 Hz, 4
H), 2.55–2.47 (m, 2 H), 1.55 (s, 3 H), 1.14 (t, J = 7.1 Hz, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 200.5, 171.0, 138.8, 124.5, 121.5,
119.4, 113.2, 102.0, 52.1, 44.9, 19.9, 11.3 ppm. HRMS (ESI) m/z
[M + H]+ calcd. for C15H21N2O2 261.1603, found 261.1588.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra of the products.
Acknowledgments
Financial support from Tongji University (20123231) is gratefully
acknowledged.
2-(4-Ethoxylcarbonylpiperazin-1-yl)-2-methylbenzofuran-3(2H)-one
(7g): Yellow oil; Rf = 0.50 (PE/AcOEt = 4:1); 106 mg (70% yield)
1H NMR (400 MHz, CDCl3): δ = 7.66 (dd, J = 11.0, 8.1 Hz, 2 H),
7.06 (t, J = 8.0 Hz, 2 H), 4.13 (dd, J = 14.1, 7.0 Hz, 2 H), 3.54 (d,
J = 17.4 Hz, 4 H), 2.88 (s, 2 H), 2.64 (s, 2 H), 1.59 (s, 3 H), 1.25
(t, J = 7.2 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 200.5,
170.6, 155.3, 138.7, 124.7, 121.5, 119.5, 113.3, 102.2, 61.3, 45.4,
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Received: November 22, 2013
Published Online: April 3, 2014
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Eur. J. Org. Chem. 2014, 3156–3162