TFA-catalyzed ring transformation of 4-hydroxycyclobutenone: A simple and general route for preparation of 3-substituted 4-aminofuran-2(5H)-ones

Article abstract of DOI:10.1039/b004654j

Following a convenient sequence of alkylation and amination of 3,4-diisopropoxycyclobutene-1,2-dione 11, three typical substituted groups (H, n-Bu, and Ph) and three typical amino groups (unsubstituted, primary and secondary) are easily introduced onto it

Full text of DOI:10.1039/b004654j

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TFA-catalyzed ring transformation of 4-hydroxycyclobutenone:
A simple and general route for preparation of 3-substituted
4-aminofuran-2(5H)-ones†
1
Jie Wang,a Xin Jiang,a Ming Chen,a Zongming Ge,a Yuefei Hu*a,b and Hongwen Hua,b
a Department of Chemistry and b Coordination Chemistry Institute, Nanjing University,
Nanjing 210093, People’s Republic of China
Received (in Cambridge, UK) 12th June 2000, Accepted 30th October 2000
First published as an Advance Article on the web 11th December 2000
Following a convenient sequence of alkylation and amination of 3,4-diisopropoxycyclobutene-1,2-dione 11, three
typical substituted groups (H, n-Bu, and Ph) and three typical amino groups (unsubstituted, primary and secondary)
are easily introduced onto its C-3 and C-4 positions, respectively, to yield 4-substituted 3-aminocyclobutene-1,2-
diones 14. Reduction of compounds 14 with NaBH4 yield 2-substituted 3-amino-4-hydroxycyclobutenones 15 in
high yields. By ring transformation of products 15 catalyzed by TFA, a simple and general route for the preparation
of 3-substituted 4-aminofuran-2(5H)-ones 4 is developed. A two-step mechanism is proposed to describe the ring
transformation of enones 15. The experimental results show that the process in refluxing p-xylene is essential for
the initial thermal electrocyclic opening of 15 to yield intermediate hydroxy ketenes 16a and 16b. They are then
lactonized in the presence of TFA to give furanones 4 in 51–94% yield.
halogeno- or 4-hydroxyfuran-2(5H)-ones can be aminated to
Introduction
yield the corresponding unsubstituted, primary and secondary
Although very few derivatives of 4-aminofuran-2(5H)-one
4-aminofuran-2(5H)-ones conveniently,1c,1d,6 the method has
occur in nature, their synthetic analogues are widely used
been limited by inaccessible precursors.8 Very few procedures
in chemical, pharmaceutical and agrochemical research. Some
can be employed for direct alkylation of 4-aminofuran-2(5H)-
4-aminofuran-2(5H)-ones have been intermediates in the
ones at C-3.6a,7
synthesis of natural products.1 Many have been patented as
To continue our agrochemical research project, a series of
3-substituted 4-aminofuran-2(5H)-ones (4 in Chart 1) were
designed as targets for synthesis. Herein, we report a novel
prodrugs or insecticides and herbicides2 (for example, see:
1–3 in Chart 1).
and practical route for the synthesis of 3-substituted 4-amino-
furan-2(5H)-ones that overcomes some of the limitations to
published procedures.
Results and discussion
Strategy
4-Hydroxycyclobutenones with an unsaturated substituent
at C-4 (5a–c in Chart 2) undergo thermal electrocyclic ring
openings to give a variety of ring-expansion products including
highly substituted phenols (6),9 quinones (7)10 and hetero-
aromatic compounds (8) (Chart 2).11
Chart 1
Many methods have been developed for the preparation of
4-aminofuran-2(5H)-ones.3–7 Using cyanohydrin derivatives as
starting materials, primary 4-aminofuran-2(5H)-ones, being
mono- or bis-substituted at C-5 to meet the requirements
of the reaction mechanism, were obtained.4 The sequence
of aminoaddition on acetylenecarboxylates followed by intra-
molecular cyclizations afforded 3-unsubstituted primary or
secondary 4-aminofuran-2(5H)-ones smoothly.5 Although 4-
† Elemental analyses results and detailed IR, MS spectra of new
compounds 14a–o, 15a–o, 4a–m and 4o are available as supplementary
data. For direct electronic access see http://www.rsc.org/suppdata/p1/
b0/b004654j/
Chart 2
66
J. Chem. Soc., Perkin Trans. 1, 2001, 66–71
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b004654j

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The effect of substituents on the direction of conrotation in
electrocyclic reactions of 4-hydroxycyclobutenones has been
explained and predicted by Houk’s work. The hydroxy group
as an electron-donating substituent favors intermediate 9 by
outward rotation (Chart 3).12 For this reason, furan-2(5H)-ones
formed by intermediate 10 in thermal electrocyclic reactions
were believed to be unusual by-products,13 even though they
were obtained as sole products in photochemistry or in metal-
catalyzed reactions.14
Chart 3
The thermal electrocyclic opening of 4-substituted 4-hydroxy-
butenones 5a–c is reversible; hence the final product might arise
from trapping intermediate 9 in an equilibrating mixture of
9 and 10. When the reactivity of R in 9 was inhibited by steric
hindrance or a hydrogen bond, the corresponding furan-2(5H)-
one was obtained by attack of the hydroxy group on the ketene
involved in the intermediate 10.13,15 It clearly implies that the
thermolysis of 5d (R = H) should yield a furan-2(5H)-one
because only the hydroxy group as trapping group is present
in the molecule. As shown in Scheme 1, this transformation
Scheme 2
cyclobutene-1,2-diones 14h–k in 55–87% yield together with
the unsymmetrical squarine by-product in around 10–15%
yield.17a Unfortunately, more than 20% of squarine by-product
was produced in the reaction between 12b and 13h (Scheme 3),
with the main product being 14k.
Scheme 3
Synthesis of 2-substituted 3-amino-4-hydroxycyclobutenones 15
In the published procedure, 3-(dibenzylamino)-4-methylcyclo-
butene-1,2-dione was reduced to 3-(dibenzylamino)-4-hydroxy-
2-methylcyclobutenone by Li(t-BuO)3AlH in 85% yield.9a
Realizing that C-2 ketone in compounds 14 is a vinylogous
ketone, we used NaBH4 to replace Li(t-BuO)3AlH to furnish
this conversion. Typically, when a solution of 3-amino-4-
phenylcyclobutene-1,2-dione 14a in methanol was treated
with NaBH4 at 0 ЊC for 30 min, 3-amino-4-hydroxy-2-phenyl-
cyclobutenone 15a was obtained in 94% yield. In the same
way, ketones 14b–o were reduced to the corresponding acyloins
15b–o in 82–97% yield. This new procedure featured short reac-
tion time, low cost and high efficiency (Scheme 4, Table 1).
Scheme 1
has been developed as a key step for the preparation of
3-substituted 4-aminofuran-2(5H)-ones 4 in our synthetic
strategy.
Synthesis of 4-substituted 3-aminocyclobutene-1,2-diones 14
Three typical 4-substituted 3-isopropoxycyclobutene-1,2-diones
(12a–c) were chosen as starting materials, which were routinely
prepared in 65–90% yield by known procedures16 from
3,4-diisopropoxycyclobutene-1,2-dione 11. The vinylogous
ester at C-3 in the structures 12a–c made the substitution
of the isopropoxy group by various amines very easy.17 Thus,
a mixture of 3-isopropoxy-4-phenylcyclobutene-1,2-dione 12a
and ammonium hydroxide (28% solution in water, 13a) in
methanol was stirred for 30 min at room temperature, and
3-amino-4-phenylcyclobutene-1,2-dione 14a was separated in
96% yield. To explore the scope of the reaction, allylic, benzyl
and cyclic amines (13b–g) were tested and all of them gave
excellent yields (14b–g, 88–96%) (Scheme 2).
Scheme 4
Synthesis of 3-substituted 4-aminofuran-2(5H)-ones 4
Following published procedures,13c,15 4-hydroxy-2-phenyl-3-
pyrrolidinocyclobutenone 15f was refluxed in p-xylene until
it disappeared completely by TLC. To our disappointment,
this process took 46 h and the desired product, 3-phenyl-4-
pyrrolidinofuran-2(5H)-one 4f, was separated in 24% yield by
column chromatography (Scheme 5). The low yield may reflect
the fact that the electrocyclic opening of 15f favors ‘unsuitable’
intermediate 16b by outward rotation obeying Houk’s theory.
Then 16b was converted into ‘suitable’ intermediate 16a though
Similarly, diones 12b,c were treated with amines 13 to give
14h–o in moderate to high yields (55–98%) (Scheme 2 and
Table 1). It was noted that the amination of 4-n-butyl-
substituted compound 12b usually gave 4-n-butyl-3-amino-
J. Chem. Soc., Perkin Trans. 1, 2001, 66–71
67

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Table 1 Substituents and yields of compounds 14, 15, and 4
Table 2 Effects of catalysts on the reaction of 15f
R2 (R1 = H)
14
(%)
15
(%)
4
(%)
Time
Catalysts
mol%
Time (t/h)
4f (%)
No.
R
or R1R2
(t/h)a
AlCl3
5
5
5
18
36
3
28b
40b
30b
75a
98b
34b
42b
ZnCl2
SnCl2
BF3–Et2O
H2SO4
HOAc
TsOH
TFA
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
Ph
Ph
Ph
Ph
Ph
Ph
Ph
n-Bu
n-Bu
n-Bu
n-Bu
H
H
H
H
96
95
95
91
96
93
88
87
82
82
55
90
96
98
91
94
91
93
94
93
89
82
97
95
89
89
96
94
92
89
84
72
82
80
70
68
62
51
69
57
61
94
72
74
69
4.0
3.0
2.0
2.5
3.0
2.5
3.0
3.0
2.5
3.0
4.0
0.5
0.25
2.5
1.0
H2C᎐CHCH2
᎐
5
2
3-CH3C6H4CH2
3-CF3C6H4CH2
4-CF3OC6H4CH2
(CH2)4
(CH2)2O(CH2)2
3-CF3OC6H4CH2
4-FC6H4CH2
3-CF3C6H4CH2
(CH2)5
100
100
100
110
200
0.5
46
10
2.5
2.0
68b
b
TFA
a An oxidized product was obtained. b Compound 15f disappeared
completely on TLC.
4-ClC6H4CH2
3-FC6H4CH2
(CH2)4
H
(CH2)2O(CH2)2
a Reaction time for 4.
Scheme 7
Scheme 5
Scheme 8
was completed within 10 h in 42% yield. The best results were
obtained in the presence of 1.1 mole equivalents of trifluoro-
acetic acid (TFA). Thus, a mixture of 15f (1.0 eq.) and TFA
(1.1 eq.) in p-xylene was refluxed for 2.5 h gave 4f in 68% yield
(Scheme 8). An attempt to decrease the reaction temperature
failed. For example, 15f was recovered completely after being
refluxed in THF for 12 h, even though 2.0 equivalents of
TFA were used. This result strongly supported the two-step
mechanism proposed in Scheme 6. Similarly, 14a–o were
converted to the corresponding lactones 4a–o in 51–94% yield
under the same conditions (Table 1).
In conclusion, we have developed a simple and general route
for preparation of 3-substituted 4-aminofuran-2(5H)-ones. The
typical substituted groups, such as H, n-Bu, and Ph on C-3 were
introduced easily. The derivatives with unsubstituted, primary
and secondary amines substituted on C-4 can all be obtained
in satisfactory yields.
Scheme 6
Experimental
a reversible equilibration illustrated in Scheme 6. Finally, an
intramolecular cyclization occurred to give target compound 4
by an attack of the hydroxy group on the ketene in 16a.
Since the intermediates 16b and 16a were hypothesized, the
intramolecular cyclization between ketene and hydroxy group
should be the key step to affect the reaction time and yield.
It has been well known that the reaction between a ketene and
a hydroxy group could be promoted significantly by acids
and Lewis acids with variable results.18 Herein, several typical
acids and Lewis acids were employed to test their effects on
this conversion. As shown in Table 2, the lactonization can be
accelerated by most Lewis acids, but without improvement
in the yield. Reagents BF3–Et2O and H2SO4 induced an altern-
ative result to give the oxidized product 3-phenyl-4-pyrrol-
idinocyclobutene-1,2-dione 14f (73 and 98% yield respectively)
(Scheme 7).
All mps were determined on a Yanaco melting point apparatus
and are uncorrected. IR spectra were recorded on a Nicolet
FT-IR 5DX spectrometer for samples as KBr pellets. 1H
NMR spectra were recorded on a Bruker MD500 or MD300
spectrometer with TMS as internal reference in CDCl3 unless
otherwise specified. J-Values are given in Hz. MS spectra were
obtained on a VG-ZAB-HS mass spectrometer with 70 eV.
Elemental analyses were performed on a Perkin-Elmer 240C
instrument and satisfactory results obtained (C 0.29, H
0.0.24, N 0.0.27%) for all new compounds 14a–m, 15a–o,
4a–m and 4o. Light petroleum refers to the fraction with dis-
tillation range 60–90 ЊC.
General procedure for preparation of 4-substituted 3-amino-
cyclobutene-1,2-diones 14
Acetic acid did not benefit either the reaction time or the
yield of the reaction. However, the reaction catalyzed by TsOH
A mixture of a 4-substituted 3-isopropoxycyclobutene-1,2-
dione 12 (10 mmol) and an amine 13 (10 mmol) in methanol
68
J. Chem. Soc., Perkin Trans. 1, 2001, 66–71

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(30 cm3) was stirred for 30 min (monitored by TLC). Then it
was poured into water (40 cm3) and the resultant mixture was
extracted with EtOAc (3 × 40 cm3). The combined organic
layers were washed successively with water (40 cm3) and brine
(40 cm3) and dried over MgSO4. The solvent was removed to
give the crude product 14, which was purified by chroma-
tography or recrystallization.
1.74 (s, 6H), 1.67–1.59 (m, 2H), 1.51–1.35 (m, 2H), 0.93 (t,
J 7.3, 3H); m/z 221 (Mϩ, 4%), 164 (100).
3-(4-Chlorobenzylamino)cyclobutene-1,2-dione 14l. Mp 118–
119 ЊC (from benzene); νmax/cmϪ1 1777, 1741; δH 7.93 (s, 1H),
7.39–7.36 (m, 2H), 7.27–7.24 (m, 2H), 4.50 (s, 2H); m/z 221
(Mϩ, 3%), 68 (100).
3-Amino-4-phenylcyclobutene-1,2-dione 14a. Mp 257 ЊC
(from EtOH–light petroleum) (Found: C, 69.20; H, 4.18; N,
8.09. C10H7NO2 requires C, 69.36; H, 4.07; N, 8.09%); νmax/cmϪ1
3316, 3119, 1791, 1721, 1661, 1600; δH (CD3OD) 7.99–7.97 (m,
2H), 7.53–7.47 (m, 3H); m/z 173 (Mϩ, 13%), 145 (20), 117 (100),
104 (15), 89 (34), 77 (4), 63 (13), 51 (6).
3-(3-Fluorobenzylamino)cyclobutene-1,2-dione 14m. Mp 69–
70 ЊC (from benzene); νmax/cmϪ1 1779, 1751; δH 7.93 (s, 1H),
7.40–7.00 (m, 4H), 4.87 (s, 1H), 4.52 (s, 2H); m/z 205 (Mϩ, 4%),
68 (100).
3-Pyrrolidinocyclobutene-1,2-dione 14n. Mp 104–105 ЊC
(from benzene–light petroleum) (lit.,19 99 ЊC). Although 14n
had a quite different mp from that of the reference material,
it had exactly the same spectral data: νmax/cmϪ1 1775, 1745;
δH 7.90 (s, 1H), 3.90–3.86 (m, 2H), 3.54–3.48 (m, 2H), 2.07–2.05
(m, 4H).
3-Allylamino-4-phenylcyclobutene-1,2-dione 14b. Mp 189–
191 ЊC (from EtOH–light petroleum); νmax/cmϪ1 1779, 1724;
δH (acetone-d6) 8.02–8.00 (m, 2H), 7.54–7.46 (m, 3H), 6.08–6.02
(m, 1H), 5.33 (d, J 17.1, 1H), 5.20 (d, J 9.9, 1H), 4.48 (d, J 4.9,
2H); m/z 213 (Mϩ, 27%), 89 (100).
3-Morpholinocyclobutene-1,2-dione 14o. Mp 151–152 ЊC
(from n-PrOH) (lit.,19 141 ЊC). Although 14o had a quite
different mp from that of the reference material, it had exactly
the same spectral data: νmax/cmϪ1 1779, 1739; δH 7.91 (s, 1H),
3.90–3.84 (m, 6H), 3.46–3.40 (m, 2H).
3-(3-Methylbenzylamino)-4-phenylcyclobutene-1,2-dione 14c.
Mp 235–237 ЊC (from EtOH–light petroleum); νmax/cmϪ1 1772,
1718; δH (acetone-d6) 8.01–8.00 (m, 2H), 7.51–7.45 (m, 3H),
7.27–7.23 (m, 3H), 7.14–7.13 (m, 1H), 5.04 (s, 2H), 2.32 (s,
3H); m/z 277 (Mϩ, 59%), 105 (100).
General procedure for preparation of 2-substituted 3-amino-4-
hydroxycyclobutenones (15)
3-Phenyl-4-[3-(trifluoromethyl)benzylamino]cyclobutene-
1,2-dione 14d. Mp 222–223 ЊC (from EtOH–light petroleum);
νmax/cmϪ1 1773, 1719; δH (acetone-d6) 8.00–7.99 (m, 2H), 7.83–
7.79 (m, 2H), 7.69–7.62 (m, 2H), 7.52–7.46 (m, 3H), 5.20
(s, 2H); m/z 331 (Mϩ, 20%), 89 (100).
To a stirred solution of a 4-substituted 3-aminocyclobutene-
1,2-dione 14 (15 mmol) in methanol (50 cm3) was added partly
powdered NaBH4 (1.0 g, 26 mmol) at 0 ЊC. After the reaction
mixture had been kept for another 30 min (monitored by TLC)
it was poured into ice–water (60 cm3). The resultant mixture
was extracted with EtOAc (3 × 40 cm3) and the combined
organic layers were washed successively with water (40 cm3) and
brine (40 cm3) and dried over MgSO4. The solvent was removed
to give the crude product 15, which was purified by chroma-
tography or recrystallization.
3-Phenyl-4-[4-(trifluoromethoxy)benzylamino]cyclobutene-
1,2-dione 14e. Mp 216–218 ЊC (from EtOH); νmax/cmϪ1 1781,
1722; δH (CD3OD) 7.97–7.96 (m, 2H), 7.53–7.48 (m, 5H),
7.31–7.30 (m, 2H), 5.03 (s, 2H); m/z 347 (Mϩ, 21%), 175 (100).
3-Phenyl-4-pyrrolidinocyclobutene-1,2-dione 14f. Mp 132–
133 ЊC (from EtOH–light petroleum); νmax/cmϪ1 1752, 1716;
δH (acetone-d6) 7.76–7.75 (m, 2H), 7.51–7.48 (m, 2H), 7.44–7.41
(m, 1H), 4.04 (t, J 5.4, 2H), 3.69 (d, J 5.9, 2H), 2.07–2.05
(m, 4H); m/z 227 (Mϩ, 4%), 171 (100).
3-Amino-4-hydroxy-2-phenylcyclobutenone 15a. Mp 232–
233 ЊC (decomp.) (from EtOH–light petroleum) (Found: C,
68.46; H, 5.13; N, 7.93. C10H9NO2 requires C, 68.56; H, 5.18;
N, 8.00%); νmax/cmϪ1 3285, 3237, 3102, 1734, 1661, 1600;
δH (CD3OD) 7.62–7.61 (m, 2H), 7.34–7.31 (m, 2H), 7.19–7.16
(m, 1H), 4.96 (s, 1H); m/z 175 (Mϩ, 100%), 147 (66), 130 (56),
118 (96), 102 (94), 89 (86), 77 (35), 63 (43), 51 (39), 44 (37).
3-Morpholino-4-phenylcyclobutene-1,2-dione 14g. Mp 146–
147 ЊC (from EtOH–light petroleum); νmax/cmϪ1 1778, 1731;
δH (acetone-d6) 7.63–7.44 (m, 5H), 4.11 (s, 2H), 3.85 (s, 4H),
3.70 (s, 2H); m/z 243 (Mϩ, 5%), 187 (100).
3-Allylamino-4-hydroxy-2-phenylcyclobutenone 15b. Mp 187–
189 ЊC (from EtOH–light petroleum); νmax/cmϪ1 3302, 1725;
δH (acetone-d6) 7.69–7.67 (m, 2H), 7.32–7.29 (m, 2H), 7.16–7.13
(m, 1H), 6.10–6.06 (m, 1H), 5.32 (d, J 17.1, 1H), 5.17 (d, J 10.1,
1H), 5.11 (s, 1H), 4.29–4.24 (m, 1H), 4.19–4.16 (m, 1H); m/z 215
(Mϩ, 61%), 174 (100).
3-Butyl-4-[3-(trifluoromethoxy)benzylamino]cyclobutene-1,2-
dione 14h. Mp 68–71 ЊC (from C6H6–light petroleum); νmax/cmϪ1
1780, 1722; δH 7.47–7.14 (m, 4H), 4.89 (d, J 6.3, 1H), 4.67 (d,
J 5.9, 1H), 2.54 (t, J 7.5, 2H), 1.63–1.50 (m, 2H), 1.37–1.26
(m, 2H), 0.88 (t, J 7.3, 3H); m/z 327 (Mϩ, 9%), 195 (100).
4-Hydroxy-3-(3-methylbenzylamino)-2-phenylcyclobutenone
15c. Mp 202–203 ЊC (from EtOH–light petroleum); νmax/cmϪ1
3330, 1722; δH (acetone-d6) 7.69–7.68 (m, 2H), 7.26–7.14
(m, 7H), 5.20 (s, 1H), 4.76 (s, 2H), 2.32 (s, 3H); m/z 279 (Mϩ,
21%), 105 (100).
3-Butyl-4-(4-fluorobenzylamino)cyclobutene-1,2-dione
14i.
Mp 104–105 ЊC (from benzene–light petroleum); νmax/cmϪ1
1779, 1715; δH 7.32–7.25 (m, 2H), 7.12–7.00 (m, 2H), 4.83 (d,
J 6.3, 1H), 4.60 (d, J 5.8, 1H), 2.53 (t, J 7.5, 2H), 1.64–1.53
(m, 2H), 1.38–1.29 (m, 2H), 0.90 (t, J 7.3, 3H); m/z 261 (Mϩ,
3%), 109 (100).
4-Hydroxy-2-phenyl-3-[3-(trifluoromethyl)benzylamino]-
cyclobutenone 15d. Mp 200–201 ЊC (from EtOH–light petrol-
eum); νmax/cmϪ1 3325, 1727; δH (acetone-d6) 7.85–7.81 (m,
2H), 7.69–7.62 (m, 4H), 7.31–7.28 (m, 2H), 7.16–7.13 (m, 1H),
5.28 (s, 1H), 4.94 (s, 2H); m/z 333 (Mϩ, 53%), 159 (100).
3-Butyl-4-[3-(trifluoromethyl)benzylamino]cyclobutene-1,2-
dione 14j. Mp 85–88 ЊC (from benzene–light petroleum); νmax
/
cmϪ1 1782, 1723; δH 7.57–7.43 (m, 4H), 4.91 (s, 2H), 2.52 (t,
J 7.5, 2H), 1.62–1.55 (m, 2H), 1.35–1.26 (m, 2H), 0.86 (t, J 7.3,
3H); m/z 311 (Mϩ, 4%), 159 (100).
4-Hydroxy-2-phenyl-3-[4-(trifluoromethoxy)benzylamino]-
cyclobutenone 15e. Mp 192–194 ЊC (from EtOH–light petrol-
eum); νmax/cmϪ1 3316, 1724; δH (CD3OD) 7.63–7.62 (m, 2H),
3-Butyl-4-piperidinocyclobutene-1,2-dione 14k. An oil; νmax
/
cmϪ1 1778, 1731; δH 3.94 (s, 2H), 3.52 (s, 2H), 2.65 (t, J 7.6, 2H),
J. Chem. Soc., Perkin Trans. 1, 2001, 66–71
69

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7.55–7.53 (m, 2H), 7.35–7.27 (m, 4H), 7.20–7.17 (m, 1H),
5.15 (s, 1H), 4.75 (s, 2H); m/z 349 (Mϩ, 19%), 175 (100).
solvent was removed to give the crude product 4, which was
purified by chromatography or recrystallization.
4-Hydroxy-2-phenyl-3-pyrrolidinocyclobutenone 15f. Mp
199–201 ЊC (from EtOH–light petroleum); νmax/cmϪ1 1725;
δH (acetone-d6) 7.49–7.47 (m, 2H), 7.32–7.27 (m, 2H), 7.18–7.15
(m, 1H), 5.05 (s, 1H), 4.06–4.02 (m, 1H), 3.71–3.68 (m,
1H), 3.63–3.58 (m, 1H), 3.40–3.36 (m, 1H), 2.05–1.99 (m, 4H);
m/z 229 (Mϩ, 43%), 70 (100).
4-Amino-3-phenylfuran-2(5H)-one 4a. Mp 198–200 ЊC (from
EtOH–water) (Found: C, 68.66; H, 5.26; N, 8.09. C10H9NO2
requires C, 68.56; H, 5.18; N, 8.00%); νmax/cmϪ1 3463, 3299,
3177, 1696, 1641, 1609, 1592; δH (acetone-d6) 7.55–7.52 (m,
2H), 7.38–7.35 (m, 2H), 7.22–7.20 (m, 1H), 6.11 (br s, 2H), 4.74
(s, 2H); m/z 175 (Mϩ, 100%), 146 (56), 130 (17), 118 (51), 91
(24), 77 (8), 63 (9).
4-Hydroxy-3-morpholino-2-phenylcyclobutenone 15g. Mp
195–197 ЊC (from EtOH–light petroleum); νmax/cmϪ1 3216,
1729; δH (acetone-d6) 7.40–7.19 (m, 5H), 5.11 (s, 1H), 3.80
(br s, 6H), 3.56 (br s, 2H); m/z 245 (Mϩ, 48%), 87 (100).
4-Allylamino-3-phenylfuran-2(5H)-one 4b. Mp 84–85 ЊC
(from benzene–light petroleum); νmax/cmϪ1 1708; δH 7.48–7.26
(m, 5H), 5.90–5.82 (m, 1H), 5.52 (br s, 1H), 5.29 (s, 1H), 5.25
(d, J 9.6, 1H), 4.77 (s, 2H), 3.78 (t, J 5.2, 2H); m/z 215 (Mϩ,
100%).
2-Butyl-4-hydroxy-3-[3-(trifluoromethoxy)benzylamino]-
cyclobutenone 15h. Mp 92 ЊC (from benzene); νmax/cmϪ1 3225,
1731; δH 7.39–7.12 (m, 4H), 6.15 (br s, 1H), 4.99 (s, 1H), 4.55
(d, J 5.5, 2H), 1.90 (t, J 7.8, 2H), 1.25–1.23 (m, 2H), 1.17–1.13
(m, 2H), 0.78 (t, J 7.2, 3H); m/z 329 (Mϩ, 15%), 175 (100).
4-(3-Methylbenzylamino)-3-phenylfuran-2(5H)-one 4c. Mp
98–99 ЊC (from EtOAc–light petroleum); νmax/cmϪ1 1713;
δH 7.48–7.07 (m, 9H), 5.71 (br s, 1H), 4.76 (s, 2H), 4.31 (d, J 6.1,
2H), 2.36 (s, 3H); m/z 279 (Mϩ, 18%), 106 (100).
2-Butyl-4-hydroxy-3-(4-fluorobenzylamino)cyclobutenone 15i.
Mp 113–114 ЊC (from benzene); νmax/cmϪ1 3239, 1735; δH 7.29–
7.25 (m, 2H), 7.04–6.94 (m, 2H), 6.16 (br s, 1H), 4.95 (s, 1H),
4.50 (d, J 5.6, 2H), 1.91 (t, J 7.5, 2H), 1.28–1.14 (m, 4H), 0.80
(t, J 7.3, 3H); m/z 263 (Mϩ, 6%), 109 (100).
3-Phenyl-4-[3-(trifluoromethyl)benzylamino]furan-2(5H)-one
4d. Mp 125.5–127 ЊC (from EtOAc–light petroleum); νmax/cmϪ1
1714; δH 7.61–7.24 (m, 9H), 5.80 (s, 1H), 4.74 (s, 2H), 4.40
(s, 2H); m/z 333 (Mϩ, 40%), 159 (100).
3-Phenyl-4-[4-(trifluoromethoxy)benzylamino]furan-2(5H)-
one 4e. Mp 126–127 ЊC (from benzene–light petroleum);
νmax/cmϪ1 1714; δH 7.46–7.21 (m, 9H), 5.87 (s, 1H), 4.72 (s, 2H),
4.34 (s, 2H); m/z 349 (Mϩ, 72%), 175 (100).
2-Butyl-4-hydroxy-3-[3-(trifluoromethyl)benzylamino]cyclo-
butenone 15j. Mp 133 ЊC (from benzene); νmax/cmϪ1 3234, 1731;
δH (CD3OD) 7.69–7.54 (m, 4H), 5.00 (s, 1H), 4.67 (s, 2H), 2.04
(t, J 7.6, 2H), 1.49–1.44 (m, 2H), 1.36–1.29 (m, 2H), 0.90 (t,
J 7.3, 3H); m/z 313 (Mϩ, 12%), 159 (100).
3-Phenyl-4-pyrrolidinofuran-2(5H)-one 4f. Mp 129–131 ЊC
(from EtOAc–light petroleum); νmax/cmϪ1 1710; δH 7.34–7.24
(m, 5H), 4.74 (s, 2H), 3.17 (br s, 4H), 1.88 (br s, 4H); m/z 229
(Mϩ, 67%), 70 (100).
2-Butyl-4-hydroxy-3-piperidinocyclobutenone 15k. Mp 84–
86 ЊC (from benzene); νmax/cmϪ1 3244, 1737; δH 5.05 (s, 1H),
3.65 (s, 2H), 3.48 (s, 2H), 2.11 (t, J 7.6, 2H), 1.70 (s, 6H), 1.50–
1.40 (m, 2H), 1.37–1.26 (m, 2H), 0.89 (t, J 7.3, 3H); m/z 223
(Mϩ, 0.6%), 57 (100).
4-Morpholino-3-phenylfuran-2(5H)-one 4g. Mp 189–190 ЊC
(from benzene–light petroleum); νmax/cmϪ1 1713; δH 7.38–7.27
(m, 5H), 4.78 (s, 2H), 3.66 (t, J 4.8, 4H), 3.18 (t, J 4.8, 4H);
m/z 245 (Mϩ, 56%), 40 (100).
3-(4-Chlorobenzylamino)-4-hydroxycyclobutenone 15l. Mp
148–150 ЊC (from MeOH–water); νmax/cmϪ1 3230, 1728;
δH (CDCl3–CD3OD) 7.35–7.33 (m, 2H), 7.30–7.25 (m, 2H),
4.93 (s, 1H), 4.43–4.35 (m, 1H), 4.27 (s, 2H); m/z 223 (Mϩ,
16%), 125 (100).
3-Butyl-4-[3-(trifluoromethoxy)benzylamino]furan-2(5H)-one
4h. An oil; νmax/cmϪ1 1725; δH 7.41–7.14 (m, 4H), 6.13 (br s, 1H),
4.53 (s, 2H), 4.38 (d, J 6.3, 2H), 2.15 (t, J 7.7, 2H), 1.45–1.38
(m, 2H), 1.29–1.20 (m, 2H), 0.87 (t, J 7.3, 3H); m/z 329 (Mϩ,
5%), 175 (100).
3-(3-Fluorobenzylamino)-4-hydroxycyclobutenone 15m. Mp
108–111 ЊC (from benzene); νmax/cmϪ1 3201, 1718; δH (CDCl3–
CD3OD) 7.40–7.32 (m, 1H), 7.13–7.09 (m, 1H), 7.06–7.00
(m, 2H), 4.95 (s, 1H), 4.45–4.37 (m, 1H), 4.10 (s, 2H); m/z 207
(Mϩ, 14%), 109 (100).
3-Butyl-4-(4-fluorobenzylamino)furan-2(5H)-one 4i. An oil;
νmax/cmϪ1 1723; δH 7.29–7.23 (m, 2H), 7.06–6.96 (m, 2H), 5.97
(br s, 1H), 4.53 (s, 2H), 4.32 (d, J 6.1, 2H), 2.14 (t, J 7.7, 2H),
1.45–1.38 (m, 2H), 1.26 (m, 2H), 0.87 (t, J 7.3, 3H); m/z 263
(Mϩ, 7%), 109 (100).
4-Hydroxy-3-pyrrolidinocyclobutenone 15n. Mp 133–136 ЊC
(from benzene–light petroleum); νmax/cmϪ1 3178, 1729; δH 6.04
(br s, 1H), 5.12 (s, 1H), 4.82 (s, 1H), 3.98–3.93 (m, 1H), 3.50–
3.45 (m, 1H), 3.39–3.37 (m, 2H), 2.05–2.00 (m, 4H); m/z 153
(Mϩ, 67%), 95 (100).
3-Butyl-4-[3-(trifluoromethyl)benzylamino]furan-2(5H)-one
4j. An oil; νmax/cmϪ1 1724; δH 7.57–7.48 (m, 4H), 5.94
(s, 1H), 4.54 (s, 2H), 4.41 (s, 2H), 2.16 (t, J 7.7, 2H), 1.46–1.39
(m, 2H), 1.32–1.25 (m, 2H), 0.87 (t, J 7.2, 3H); m/z 313
(Mϩ, 9%), 159 (100).
4-Hydroxy-3-morpholinocyclobutenone 15o. Mp 117–119 ЊC
(from benzene–light petroleum); νmax/cmϪ1 3232, 1725; δH 6.15
(br s, 1H), 5.17 (s, 1H), 4.93 (s, 1H), 3.86–3.81 (m, 5H), 3.64–
3.60 (m, 1H), 3.48–3.41 (m, 2H); m/z 169 (Mϩ, 68%), 55 (100).
3-Butyl-4-piperidinofuran-2(5H)-one 4k. An oil; νmax/cmϪ1
1730; δH 4.56 (s, 2H), 3.94 (s, 1H), 3.52 (s, 1H), 3.33 (s, 2H),
2.65 (t, J 7.6, 1H), 2.31 (t, J 7.3, 1H), 1.74 (s, 6H), 1.47–1.32
(m, 4H), 0.93 (t, J 7.3, 3H); m/z 223 (Mϩ, 13%), 180 (100).
General procedure for preparation of 3-substituted 4-aminofuran-
2(5H)-ones 4
A mixture of a 2-substituted 3-amino-4-hydroxycyclobutenone
15 (15 mmol) and TFA (1.88 g, 16.5 mmol) in anhydrous
p-xylene (35 cm3) was refluxed until compound 15 had dis-
appeared completely on TLC. Then it was washed with water
(35 cm3) and the organic layer was dried over MgSO4. The
4-(4-Chlorobenzylamino)furan-2(5H)-one 4l. Mp 161–162 ЊC
(from CHCl3–light petroleum); νmax/cmϪ1 1698; δH (CDCl3–
CD3OD) 7.37–7.32 (m, 2H), 7.25–7.23 (m, 2H), 4.70 (s, 2H),
4.26 (s, 2H), 3.97 (s, 1H); m/z 223 (Mϩ, 15%), 125 (100).
70
J. Chem. Soc., Perkin Trans. 1, 2001, 66–71

View Article Online
7 B. de Ancos, M. C. Maestro, M. R. Martin and A. I. Mateo,
Tetrahedron, 1994, 50, 13857.
4-(3-Fluorobenzylamino)furan-2(5H)-one 4m. Mp 165–
166.5 ЊC (from EtOAc–light petroleum); νmax/cmϪ1 1701;
δH (CDCl3–CD3OD) 7.47–7.01 (m, 4H), 4.62 (s, 1H), 4.42
(s, 2H), 4.31 (s, 2H); m/z 207 (Mϩ, 20%), 109 (100).
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S. Patil and H. W. Moore, J. Am. Chem. Soc., 1989, 111, 975;
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J. Org. Chem., 1999, 64, 4030; (g) P. Wipf and C. R. Hopkins,
J. Org. Chem., 1999, 64, 6879.
4-Pyrrolidinofuran-2(5H)-one 4n. Mp 119–121 ЊC (from
benzene) (lit.,6b 120–121 ЊC).
4-Morpholinofuran-2(5H)-one 4o. Mp 107–109 ЊC (from
benzene); νmax/cmϪ1 1714; δH 4.74 (s, 2H), 4.72 (s, 1H), 3.79 (t,
J 4.7, 4H), 3.23 (t, J 4.7, 4H); m/z 169 (Mϩ, 100%).
Acknowledgements
We are grateful to the Education Ministry of China and the
Education Department of Jiangsu Province for financial
support.
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71