Synthesis of 5-alkoxy-4-amino-3-bromo-2(5H)-furanones containing benzene rings

Article abstract of DOI:10.1007/s11164-012-0674-y

Using KF as base and THF as solvent, different 5-alkoxy-3,4-dibromo-2(5H)- furanones were reacted with amines containing a benzene ring structure by Michael addition-elimination reaction at room temperature or 40 C to give twenty-three 5-alkoxy-4-amino-3-bromo-2(5H)-furanones containing benzene rings, with yields of 21-86 % (mostly over 64 %). The structures of all the newly synthesized compounds were elucidated and confirmed by FTIR, UV, ¹H NMR, ¹³C NMR, and mass spectroscopy, elemental analysis, and X-ray single-crystal diffraction. This rapid synthesis of the series of 2(5H)-furanones derivatives with different bioactive units is not only an important synthetic strategy for 2(5H)-furanone derivatives but also a basis for synthesis of potential drug molecules for activity testing.

Full text of DOI:10.1007/s11164-012-0674-y

Res Chem Intermed (2013) 39:1153–1168
DOI 10.1007/s11164-012-0674-y
Synthesis of 5-alkoxy-4-amino-3-bromo-2
(5H)-furanones containing benzene rings
•
Fu-Ling Xue Jian-Xiao Li Zhao-Yang Wang
•
•
•
Jin-Feng Xiong Di Li
Received: 16 April 2012 / Accepted: 29 May 2012 / Published online: 27 June 2012
Ó Springer Science+Business Media B.V. 2012
Abstract Using KF as base and THF as solvent, different 5-alkoxy-3,4-dibromo-
2(5H)-furanones were reacted with amines containing a benzene ring structure by
Michael addition–elimination reaction at room temperature or 40 °C to give twenty-
three 5-alkoxy-4-amino-3-bromo-2(5H)-furanones containing benzene rings, with
yields of 21–86 % (mostly over 64 %). The structures of all the newly synthesized
compounds were elucidated and confirmed by FTIR, UV, 1H NMR, 13C NMR, and
mass spectroscopy, elemental analysis, and X-ray single-crystal diffraction. This
rapid synthesis of the series of 2(5H)-furanones derivatives with different bioactive
units is not only an important synthetic strategy for 2(5H)-furanone derivatives but
also a basis for synthesis of potential drug molecules for activity testing.
Keywords 2(5H)-Furanone Á Synthesis Á Amine Á Benzene ring structure Á
Michael addition–elimination reaction
Introduction
2(5H)-Furanones are important oxygen-containing heterocycles [1, 2]. 2(5H)-
Furanone is an important structural subunit found in many natural products (Fig. 1)
[3–6]. Many compounds containing the 2(5H)-furanone moiety have aroused great
interest because of their significant biological activity [7], for example antifungal [8,
9], anti-inflammatory [10, 11], antiviral [12], and antitumor [13–15]. Furthermore,
Electronic supplementary material The online version of this article (doi:
10.1007/s11164-012-0674-y) contains supplementary material, which is available to authorized users.
F.-L. Xue Á J.-X. Li Á Z.-Y. Wang (&) Á J.-F. Xiong Á D. Li
School of Chemistry and Environment, South China Normal University,
Guangzhou 510006, People’s Republic of China
e-mail: wangwangzhaoyang@tom.com
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F.-L. Xue et al.
O
O
O
MeO
HO
O
O
HO
O
COOMe
O
O
O
Penicillic acid
Asteriscunolide A
(+/-)-Cephalosol
OMe
Fig. 1 Some biologically active natural products bearing the 2(5H)-furanone moiety
OMe
OH
O
O
O
HO
Cl
Cl
HO
HO
O
O
HN
O
NH
OH
OH
O
O
H3CO
O
O
Aspernolide D
O
Fig. 2 Some biologically active natural or synthetic 2(5H)-furanone compounds containing benzene
rings
relatively simple 2(5H)-furanone compounds are also important organic interme-
diates [13, 16–20]. As a result, many researchers have recently devoted much
attention to 2(5H)-furanone chemistry [21–28].
Many compounds containing the benzene ring structure have biological activity
[29–32]. Some natural or synthetic 2(5H)-furanone compounds containing the
benzene ring framework (Fig. 2) have especially important biological activity,
including anti-inflammatory, antibacterial, antimitotic, and HIV-1 integrase inhib-
itory activity [9, 33–38]. Therefore, synthesis of 2(5H)-furanone derivatives
containing benzene rings has been receiving substantial attention [9, 34–37, 39–41].
In this article, in order to design and synthesize novel 2(5H)-furanone derivatives
with better biological activity, we tried to introduce benzene ring structures into
2(5H)-furanone molecules. On the basis of our previous studies on the syntheses of
serial 5-alkoxy-4-amino-3-halo-2(5H)-furanones [38], we further investigated the
reaction of 5-alkoxy-3,4-dibromo-2(5H)-furanones 1 with different amines 2
containing benzene rings, and synthesized a series of 5-alkoxy-4-amino-3-bromo-
2(5H)-furanones, 3a–3w, containing benzene rings (Scheme 1).
Results and discussion
Effects of different 2(5H)-furanone intermediates on yield
In our previous work [38] we investigated Michael addition–elimination reactions
of 5-alkoxy-3,4-dihalo-2(5H)-furanone intermediates with different compounds
containing nitrogen, for example amino acids, amino acid esters, aliphatic primary
amines, and secondary amines. Therefore, after the intermediates 5-alkoxy-3,4-
dibromo-2(5H)-furanones had been obtained [42], Michael addition–elimination
123

Synthesis of 5-alkoxy-4-amino-3-bromo-2(5H)-furanone
1155
KF, THF
Br
R1O
Br
Br
O
n
NH
r.t. or 40OC
R2
n
NH2
R2
R1O
24-120 h
O
O
O
(n = 0, 1)
2
1
3
Scheme 1 Synthetic route to target compounds 3
reactions with different amines containing benzene rings were performed in the
presence of KF, under a protective N2 atmosphere, in THF at room temperature or
40 °C (Scheme 1). The results are shown in Table 1.
It is apparent that all the 5-alkoxy-3,4-dibromo-2(5H)-furanones could be
smoothly transformed into the desired products, and most isolated yields were equal
to or better than 64 %. Of course, the steric effect of the 5-alkoxy group in the
intermediates was obvious. When the 5-substituted group was methoxy, in the
reaction with same amine 2 yields of the corresponding products were usually
higher than those of products prepared from 5-benzyloxy-3,4-dibromo-2(5H)-
furanones. For example, the biggest yield of the former was 86 % (Table 1, entry
10) whereas that of the latter was 83 % (entry 21).
Effects of different amines on yield
Similarly, when the same 5-alkoxy-3,4-dibromo-2(5H)-furanone was used it is
apparent from Table 1 that different amines containing benzene rings notably
affected the Michael addition–elimination reaction.
First, benzylamines reacted more easily than aromatic anilines with 5-alkoxy-3,4-
dibromo-2(5H)-furanones 1, providing the desired products. It is also apparent from
Table 1 that not only were all yields better when benzylamines were used, reaction
times (usually 24–48 h) of benzylamines with 5-alkoxy-3,4-dibromo-2(5H)-fura-
nones 1 were also shorter than those for aromatic anilines (usually equal to or more
than 72 h).
Second, irrespective of the benzylamine or aromatic aniline, steric hindrance
resulting from the positions of substituents was also obvious. For example, for
benzylamines, when the substituent was at the 2-position of the benzene ring (e.g.
substrate 2k), the yield was reduced (Table 1, entries 22 and 23). Thus, lower
reactivity aromatic anilines, for example o-chloroaniline, reacted slowly with
5-alkoxy-3,4-dibromo-2(5H)-furanones 1, prolonging reaction time.
Third, the type of substituent on the benzene ring also affected the yield. Usually,
electron-donating substituents were advantageous for the reaction (e.g. Table 1,
entries 12 and 13). In contrast, electron-withdrawing substituents were disadvan-
tageous. For the strongly electron-withdrawing nitro group (-NO2), reaction of
even p-nitroaniline, with low steric hindrance, did not occur.
When the substituent on the benzene ring was a halogen, all p-halo substituted
amines could be smoothly transformed into the desired products. However, the
yields of the products were low (21–64 %). For the same kinds of amine and
5-alkoxy-3,4-dibromo-2(5H)-furanones 1, yields from p-fluoro-substituted amines
123

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F.-L. Xue et al.
Table 1 Yields of the target compounds 3 obtained by reaction of 5-alkoxy-3,4-dibromo-2(5H)-fura-
nones 1 with amines 2 containing benzene rings
Time
(h)
Yield
(%)
Entry Intermedisates 1
Amines 2
Compounds 3
1
72
60
75
80
1a
2a
3a
2
1a
1a
1a
1a
1a
2b
2c
3b
3c
3
72
96
78
64
52
36
4
2d
2e
2f
3d
3e
3f
5
120
120
6
123

Synthesis of 5-alkoxy-4-amino-3-bromo-2(5H)-furanone
Table 1 continued
1157
Cl
HN
H3CO
Br
7
8
1a
1a
120
120
46
41
O
O
2g
2h
3g
3h
9
1a
24
24
84
86
2i
2j
3i
MeO
HN
Br
10
1a
1a
H3CO
O
O
3j
11
12
24
72
67
66
2k
2a
3k
3l
1b
123

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F.-L. Xue et al.
Table 1 continued
13
14
15
16
17
18
1b
2b
2c
2d
2e
2f
72
72
76
3m
3n
1b
1b
1b
1b
1b
72
43
31
21
26
96
3o
3p
120
120
120
3q
3r
2g
123

Synthesis of 5-alkoxy-4-amino-3-bromo-2(5H)-furanone
Table 1 continued
1159
19
20
1b
1b
2h
120
22
78
3s
HN
Br
2i
30
PhH2CO
O
O
3t
21
1b
2j
24
83
3u
3v
22
23
1b
1b
2k
48
48
64
76
2l
3w
were usually the best, and yields from p-bromo-substituted amines were the worst
(Table 1, entries 4–6 and 15–17).
Characterization of the structures of the new compounds
In the IR spectra, stretching absorption of the N–H groups was observed in the
region 3,300–3,100 cm-1 whereas stretching absorption bands of saturated C–H
123

1160
F.-L. Xue et al.
Fig. 3 X-ray structure of
compound 3d
were observed in the region 2,980–2,820 cm-1. The strong C=O stretching band
appeared at 1,760–1,720 cm-1 and the C=C stretching band occurred in the region
1,650–1,600 cm-1
.
The existence of C=O and C=C groups was also proved by UV spectroscopy—
there were strong absorption peaks in the 240–300 nm region caused by the p ? p*
transition of the C=C–C=O conjugated system in the 2(5H)-furanone ring.
1
In H NMR, there was a singlet at 5.65–6.03 ppm from the 5-H of 2(5H)-
furanone. Furthermore, the molecular structure of product 3d was confirmed by
X-ray analysis (Fig. 3). Combined with data from other structure characterization, it
was apparent the furanone ring was not opened under these experimental
conditions.
This characterization not only proved the structures of the twenty-two
newly synthesized compounds were as expected, it also showed that the
concise and effective synthetic method for 2(5H)-furanone derivatives
containing benzene rings had wide applicability and broad tolerance of
different substituent groups.
Conclusion
In summary, twenty-three 5-alkoxy-4-amino-3-bromo-2(5H)-furanones containing
benzene rings were designed and efficiently synthesized under very mild reaction
conditions. These target compounds with multiple bioactive moieties will afford a
basis for activity testing of potential drug molecules. Many conversions could be
carried out by use of C–X in the benzene ring [11, 43–45]. Thus, these 5-alkoxy-4-
amino-3-bromo-2(5H)-furanones are also important intermediates for more 2(5H)-
furanone derivatives with polyfunctional groups.
123

Synthesis of 5-alkoxy-4-amino-3-bromo-2(5H)-furanone
1161
Experimental
General
All melting points were determined on an X-5 digital melting point apparatus and
are uncorrected. Infrared spectra were recorded on a Bruker Vector 33 FT-IR
instrument, by the liquid film method, in the absorption range 4,000–400 cm-1
.
1H and 13C NMR spectra were obtained in CDCl3 on a Varian DRX-400 MHz
spectrometer, and tetramethylsilane (TMS) was used as internal standard. UV
absorption peaks were measured by use of a Shimazu UV-2550 ultraviolet
absorption detector with dichloromethane as solvent. Elemental analysis was
performed with a Thermo Flashea TM 112 elemental analyzer. Mass spectra (MS)
were recorded on a Thermo LCQ DECA XP MAX mass spectrometer.
All reagents and solvents were commercially available and used as received.
Using furfural, benzyl alcohol, and methanol as starting materials, the intermediate
5-alkoxy-3,4-dibromo-2(5H)-furanones 1a and 1b were prepared in accordance with
the literature [38, 42].
Typical procedure for synthesis of target compounds 3a–3w
5-Alkoxy-3,4-dibromo-2(5H)-furanone 1 (1 mmol) in THF (3 mL) was stirred with
KF (3 mmol) under an atmosphere of N2. Subsequently, the appropriate amine 2
containing a benzene ring was added at room temperature or 40 °C. After
completion of the reaction, as indicated by TLC, the reaction mixture was cooled to
room temperature, diluted with CH2Cl2 (10 mL), and then washed with saturated
salt solution (10 mL). The aqueous layer was extracted with CH2Cl2 (10 mL 9 2).
The organic layers were combined and dried over MgSO4. The solvent was removed
under reduced pressure then the residue was purified by flash chromatography on
silica gel to afford compounds 3a–3w for analysis.
3-Bromo-5-methoxy-4-phenylaminofuran-2(5H)-one (3a)
Yellow solid, yield 75 %; m.p. 116.2–116.8 °C (115–117 °C [46]); UV–visible
1
(CH2Cl2) kmax: 288 nm; H NMR (400 MHz, CDCl3-TMS) d: 3.41 (3H, s, CH3O-
6), 5.92 (1H, s, CH-5), 7.14 (1H, s, NH-7), 7.19 (2H, d, J = 8.0 Hz, ArH-9, 13),
7.25 (1H, t, J = 8.0 Hz, ArH-11), 7.36–7.40 (2H, m, ArH-10, 12); 13C NMR
(100 MHz, CDCl3-TMS), d: 55.7, 78.7, 99.2, 123.6, 126.4, 129.3, 136.6, 156.8,
167.7; IR (film) m: 3265, 3059, 2936, 2841, 1748, 1644, 1595, 1536, 1498, 1450,
1320, 1191, 1127, 950, 747, 712, 577; ESI–MS m/z (%): 282 ([M - H]-, 100.0);
Anal. Calcd for C11H10BrNO3: C 46.50, H 3.55, N 4.93, Found: C 46.22, H 3.72, N
4.66.
3-Bromo-5-methoxy-4-(4-methoxyphenyl)aminofuran-2(5H)-one (3b)
1
Reddish brown liquid, yield 80 %; UV–visible (CH2Cl2) kmax: 286 nm; H NMR
(400 MHz, CDCl3-TMS) d: 3.39 (3H, s, CH3O-6), 3.82 (3H, s, CH3O-14), 5.80 (1H,
123

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F.-L. Xue et al.
s, CH-5), 6.89 (2H, d, J = 8.0 Hz, ArH-10, 12), 7.05 (1H, s, NH-7), 7.14 (2H, d,
J = 8.0 Hz, ArH-9, 13); 13C NMR (100 MHz, CDCl3-TMS) d: 55.5, 55.6, 77.0,
99.0, 114.2, 126.4, 129.1, 157.6, 158.3, 167.9; IR (film) m: 3266, 3049, 2936, 2839,
1754, 1644, 1513, 1463, 1443, 1324, 1246, 1190, 1129, 950, 830, 521; ESI–MS
m/z (%): 312 ([M - H]-, 95.3); Anal. Calcd for C12H12BrNO4: C 45.88, H 3.85, N
4.46, Found: C 45.97, H 3.69, N 4.52.
3-Bromo-4-(3,4-dimethylphenyl)amino-5-methoxyfuran-2(5H)-one (3c)
White solid, yield 78 %; m.p. 115.7–116.1 °C; UV–visible (CH2Cl2) kmax: 289 nm;
1H NMR (400 MHz, CDCl3-TMS) d: 2.25 (3H, s, CH3-14), 2.26 (3H, s, CH3-15),
3.41 (3H, s, CH3O-6), 5.89 (1H, s, CH-5), 6.90–6.94 (2H, m, ArH-9, 13), 6.96 (1H,
s, NH-7), 7.12 (1H, d, J = 8.0 Hz, ArH-12); 13C NMR (100 MHz, CDCl3-TMS) d:
19.3, 19.9, 55.4, 78.1, 99.0, 120.9, 124.9, 130.2, 134.2, 135.0, 137.7, 157.0, 167.6;
IR (film) m: 3280, 3027, 2921, 2852, 1748, 1642, 1610, 1505, 1446, 1325, 1196,
1127, 1008, 831, 746, 513; ESI–MS m/z (%): 310 ([M - H]-, 67.3); Anal. Calcd
for C13H14BrNO3: C 50.02, H 4.52, N 4.49, Found: C 49.88, H 4.71, N 4.62.
3-Bromo-4-(4-fluorophenyl)amino-5-methoxyfuran-2(5H)-one (3d)
Yellow solid, yield 64 %; m.p. 140.1–140.4 °C; UV–visible (CH2Cl2) kmax
:
1
283 nm; H NMR (400 MHz, CDCl3-TMS) d: 3.42 (3H, s, CH3O-6), 5.84 (1H, s,
CH-5), 7.04–7.11 (2H, m, ArH-9, 13), 7.17–7.23 (2H, m, ArH-10, 12), 7.28 (1H, s,
NH-7); 13C NMR (100 MHz, CDCl3-TMS) d: 55.8, 77.8, 99.2, 116.0, 126.5, 132.4,
157.0, 161.0, 168.0; IR (film) m: 3263, 3054.9, 2921, 2849, 1750, 1645, 1604, 1509,
1446, 1325, 1221, 1189, 1128, 951, 835, 505; ESI–MS m/z (%): 300 ([M - H]-,
97.3); Anal. Calcd for C11H9BrFNO3: C 43.73, H 3.00, N 4.64, Found: C 43.86, H
3.24, N 4.41.
3-Bromo-4-(4-chlorophenyl)amino-5-methoxyfuran-2(5H)-one (3e)
1
White oil, yield 52 %; UV–visible (CH2Cl2) kmax: 293 nm; H NMR (400 MHz,
CDCl3-TMS) d: 3.45 (3H, s, CH3O-6), 5.88 (1H, s, CH-5), 6.84 (1H, s, NH-7), 7.13
(2H, d, J = 8.0 Hz, ArH-9, 13), 7.36 (2H, d, J = 8.0 Hz, ArH-10, 12); 13C NMR
(100 MHz, CDCl3-TMS) d: 55.7, 79.8, 99.0, 124.8, 129.4, 131.9, 135.1, 156.3,
167.1; IR (film) m: 3263, 3049, 2921, 2849, 1750, 1642, 1593, 1523, 1492, 1468,
1320, 1190, 1128, 977, 820, 746, 501; ESI–MS m/z (%): 316 ([M - H]-, 89.7);
Anal. Calcd for C11H9BrClNO3: C 41.47, H 2.85, N 4.40, Found: C 41.62, H 2.61,
N 4.29.
3-Bromo-4-(4-bromophenyl)amino-5-methoxyfuran-2(5H)-one (3f)
Yellowish solid, yield 36 %; m.p. 117.0–117.5 °C; UV–visible (CH2Cl2) kmax
:
1
294 nm; H NMR (400 MHz, CDCl3-TMS) d: 3.45 (3H, s, CH3O-6), 5.88 (1H, s,
CH-5), 6.98 (1H, s, NH-7), 7.07 (2H, d, J = 8.0 Hz, ArH-9, 13), 7.50 (2H, d,
J = 8.0 Hz, ArH-10, 12); 13C NMR (100 MHz, CDCl3-TMS) d: 55.8, 79.8, 99.1,
123

Synthesis of 5-alkoxy-4-amino-3-bromo-2(5H)-furanone
1163
119.6, 125.1, 132.3, 135.7, 156.2, 167.3; IR (film) m: 3266, 3055, 2921, 2846, 1747,
1640, 1587, 1534, 1489, 1324, 1188, 1127, 1010, 817, 502; ESI–MS m/z (%): 360
([M - H]-, 57.7); Anal. Calcd for C11H9Br2NO3: C 36.40, H 2.50, N 3.86, Found:
C 36.58, H 2.59, N 4.00.
3-Bromo-4-(3-chlorophenyl)amino-5-methoxyfuran-2(5H)-one (3g)
Yellow solid, yield 46 %; m.p. 139.5–140.5 °C; UV–visible (CH2Cl2) kmax
:
291 nm; 1H NMR (400 MHz, CDCl3-TMS) d: 3.48 (3H, s, CH3-6), 5.92 (1H, s, CH-
5), 6.88 (1H, s, NH-7), 7.07 (1H, d, J = 8.0 Hz, ArH-13), 7.19–7.25 (2H, m, ArH-9,
11), 7.29–7.35 (1H, m, ArH-12); 13C NMR (100 MHz, CDCl3-TMS) d: 55.8, 80.7,
99.1, 121.1, 123.2, 126.3, 130.3, 134.9, 137.8, 156.0, 167.0; IR (film) m: 3263, 3060,
2933, 2841, 1751, 1643, 1593, 1536, 1480, 1329, 1191, 1128, 955, 778, 746, 688,
543; ESI–MS m/z (%): 316 ([M - H]-, 86.3); Anal. Calcd for C11H9BrClNO3: C
41.47, H 2.85, N 4.40, Found: C 41.31, H 3.00, N 4.59.
3-Bromo-5-methoxy-4-(naphthalen-1-ylamino)furan-2(5H)-one (3h)
Brown solid, yield 41 %; m.p. 143.5–144.3 °C; UV–visible (CH2Cl2) kmax: 296 nm;
1H NMR (400 MHz, CDCl3-TMS) d: 3.30 (3H, s, CH3O-6), 5.77 (1H, s, CH-5),
6.80 (1H, s, NH-7), 7.42 (1H, d, J = 8.0 Hz, ArH-9), 7.47–7.53 (1H, m, ArH-10),
7.56–7.64 (2H, m, ArH-16, 17), 7.87 (1H, d, J = 8.0 Hz, ArH-11), 7.93 (2H, d,
J = 8.0 Hz, ArH-14, 15); 13C NMR (100 MHz, CDCl3-TMS) d: 55.7, 77.2, 99.1,
121.7, 123.9, 125.2, 126.9, 127.4, 128.3, 128.7, 129.8, 132.1, 134.2, 157.9, 167.2;
IR (film) m: 3358, 3038, 2922.68, 2852, 1747, 1644, 1597, 1575, 1506, 1331, 1202,
1128, 1005, 793, 773, 747, 522; ESI–MS m/z (%): 332 ([M - H]-, 100.0); Anal.
Calcd for C15H12BrNO3: C 53.91, H 3.62, N 4.19, Found: C 53.84, H 3.75, N 4.27.
3-Bromo-5-methoxy-4-(4-methylbenzyl)aminofuran-2(5H)-one (3i)
Colorless liquid, yield 84 %; UV–visible (CH2Cl2) kmax: 275 nm; 1H NMR
(400 MHz, CDCl3-TMS) d: 2.35 (3H, s, CH3-15), 3.48 (3H, s, CH3O-6), 4.59 (2H,
s, CH2-8), 5.65 (2H, s, CH-5, NH-7), 7.19 (4H, s, ArH-10, 11, 13, 14); 13C NMR
(100 MHz, CDCl3-TMS) d: 21.2, 47.3, 55.2, 77.4, 98.2, 127.5, 129.7, 133.8, 138.0,
159.2, 167.6; IR (film) m: 3319, 3093, 3005, 2922, 2846, 1751, 1645, 1578, 1516,
1445, 1324, 1202, 1126, 977, 805, 508; ESI–MS m/z (%): 310 ([M - H]-, 40.8);
Anal. Calcd for C13H14BrNO3: C 50.02, H 4.52, N 4.49, Found: C 50.13, H 4.48, N
4.35.
3-Bromo-5-methoxy-4-(4-methoxybenzyl)aminofuran-2(5H)-one (3j)
Yellowish oil, yield 86 %; UV–visible (CH2Cl2) kmax: 277 nm; 1H NMR
(400 MHz, CDCl3-TMS) d: 3.48 (3H, s, CH3O-6), 3.81 (3H, s, CH3O-15), 4.57
(2H, s, CH2-8), 5.62 (1H, s, NH-7), 5.66 (1H, s, CH-5), 6.91 (2H, d, J = 8.0 Hz,
ArH-11, 13), 7.24 (2H, d, J = 8.0 Hz, ArH-10, 14); 13C NMR (100 MHz, CDCl3-
TMS) d: 47.1, 55.2, 55.4, 77.4, 98.4, 114.3, 128.8, 129.0, 159.4, 167.7; IR (film) m:
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F.-L. Xue et al.
3315, 3082, 2922, 2839, 1749, 1642, 1586, 1513, 1442, 1322, 1249, 1176, 1124,
975, 819, 515; ESI–MS m/z (%): 326 ([M - H]-, 100.0); Anal. Calcd for
C13H14BrNO4: C 47.58, H 4.30, N 4.27, Found: C 47.64, H 4.49, N 4.13.
3-Bromo-4-(2-chlorobenzyl)amino-5-methoxyfuran-2(5H)-one (3k)
Yellowish solid, yield 67 %; m.p. 131.4–133.1 °C; UV–visible (CH2Cl2) kmax
:
1
274 nm; H NMR (400 MHz, CDCl3-TMS) d: 3.50 (3H, s, CH3O-6), 4.60–4.85
(2H, m, CH2-8), 5.54 (1H, s, NH-7), 5.73 (1H, s, CH-5), 7.29–7.44 (4H, m, ArH-11,
12, 13, 14); 13C NMR (100 MHz, CDCl3-TMS) d: 45.4, 55.1, 77.3, 98.2, 127.5,
129.3, 129.7, 129.9, 133.3, 134.4, 158.7, 167.3; IR (film) m: 3301, 3073, 2933, 2841,
1752, 1646, 1573, 1528, 1444, 1323, 1202, 1128, 977, 748, 514; ESI–MS m/z (%):
332 ([M - H]-, 100.0); Anal. Calcd for C12H11BrClNO3: C 43.34, H 3.33, N 4.21,
Found: C 43.21, H 3.15, N 4.38.
5-Benzyloxy-3-bromo-4-phenylaminofuran-2(5H)-one (3l)
Yellow solid, yield 66 %; m.p. 142.3–143.4 °C; UV–visible (CH2Cl2) kmax
:
1
290 nm; H NMR (400 MHz, CDCl3-TMS) d: 4.50–4.74 (2H, dd, J1 = 12.0 Hz,
J2 = 12.0 Hz, CH2-6), 6.03 (1H, s, CH-5), 6.87 (1H, s, NH-7), 7.01 (2H, d,
J = 8.0 Hz, ArH-9, 13), 7.07–7.17 (3H, m, ArH-10, 11, 12), 7.25–7.29 (3H, m,
ArH-16, 17, 18), 7.33–7.37 (2H, m, ArH-15, 19); 13C NMR (100 MHz, CDCl3-
TMS) d: 71.1, 79.4, 97.1, 123.5, 126.4, 128.5, 128.5, 128.7, 129.5, 135.0, 136.8,
157.5, 167.4; IR (film) m: 3264, 3055, 3034, 2921, 2851, 1747, 1638, 1595, 1497,
1449, 1319, 1191, 1130, 1026, 746, 698, 496; ESI–MS m/z (%): 382 ([M ? Na]?,
93.7); Anal. Calcd for C17H14BrNO3: C 56.68, H 3.92, N 3.89, Found: C 56.52, H
4.01, N 4.01.
5-Benzyloxy-3-bromo-4-(4-methoxyphenyl)aminofuran-2(5H)-one (3m)
Brown liquid, yield 76 %; UV–visible (CH2Cl2) kmax: 288 nm; 1H NMR (400 MHz,
CDCl3-TMS) d: 3.82 (3H, s, CH3O-20), 4.47–4.72 (2H, dd, J1 = 12.0 Hz,
J2 = 12.0 Hz, CH2-6), 5.90 (1H, s, CH-5), 6.82 (2H, d, J = 12.0 Hz, ArH-10,
12), 6.85 (1H, s, NH-7), 6.99–7.05 (2H, m, ArH-16, 18), 7.07 (2H, d, J = 12.0 Hz,
ArH-9, 13), 7.16–7.31 (3H, m, ArH-15, 17, 19); 13C NMR (100 MHz, CDCl3-TMS)
d: 55.6, 71.0, 77.6, 96.9, 114.4, 126.5, 128.5, 128.5, 128.6, 129.3, 135.1, 158.3,
158.4, 167.7; IR (film) m: 3265, 3035, 2921, 2850, 1748, 1641, 1588, 1513, 1455,
1326, 1246, 1192, 1130, 948, 829, 746, 699, 514; ESI–MS m/z (%): 390 ([M ? H]?,
27.3), 412 ([M ? Na]?, 95.0); Anal. Calcd for C18H16BrNO4: C 55.40, H 4.13, N
3.59, Found: C 55.54, H 4.29, N 3.39.
5-Benzyloxy-3-bromo-4-(3,4-dimethylphenyl)aminofuran-2(5H)-one (3n)
1
Yellow oil, yield 72 %; UV–visible (CH2Cl2) kmax: 290 nm; H NMR (400 MHz,
CDCl3-TMS) d: 2.21 (3H, s, CH3-20), 2.27 (3H, s, CH3-21), 4.47–4.73 (2H, dd,
J1 = 12.0 Hz, J2 = 12.0 Hz, CH2-6), 5.98 (1H, s, CH-5), 6.75 (1H, s, NH-7), 6.86
123

Synthesis of 5-alkoxy-4-amino-3-bromo-2(5H)-furanone
1165
(1H, d, J = 8.0 Hz, ArH-9), 6.89 (1H, s, ArH-13), 6.96–7.02 (2H, m, ArH-16, 18),
7.09 (1H, d, J = 8.0 Hz, Ar–H-10), 7.24–7.36 (3H, m, Ar–H-15, 17, 19); 13C NMR
(100 MHz, CDCl3-TMS) d: 19.4, 19.9, 71.0, 78.4, 97.0, 121.3, 125.2, 128.4, 128.4,
128.6, 130.4, 134.3, 135.1, 135.3, 137.9, 157.9, 167.5; IR (film) m: 3265, 3027,
2925, 2852, 1749, 1641, 1612, 1505, 1454, 1322, 1198, 1129, 956, 823, 746, 698,
513; ESI–MS m/z (%): 388 ([M ? H]?, 8.3), 410 ([M ? Na]?, 100.0); Anal. Calcd
for C19H18BrNO3: C 58.78, H 4.67, N 3.61, Found: C 58.88, H 4.80, N 3.52.
5-Benzyloxy-3-bromo-4-(4-fluorophenyl)aminofuran-2(5H)-one (3o)
White solid, yield 43 %; m.p. 150.4–152.2 °C; UV–visible (CH2Cl2) kmax: 283 nm;
1H NMR (400 MHz, CDCl3-TMS) d: 4.51–4.75 (2H, dd, J1 = 12.0 Hz,
J2 = 12.0 Hz, CH2-6), 5.92 (1H, s, CH-5), 6.77 (1H, s, NH-7), 7.00 (2H, d,
J = 8.0 Hz, ArH-9, 13), 7.04 (2H, d, J = 8.0 Hz, ArH-10, 12), 7.05–7.21 (3H, m,
ArH-16, 17, 18), 7.28–7.33 (2H, m, ArH-15, 19); 13C NMR (100 MHz, CDCl3-
TMS) d: 71.1, 78.9, 96.7, 116.2, 126.4, 128.6, 128.6, 128.7, 132.5, 134.9, 157.6,
161.1, 167.4; IR (film) m: 3274, 3060, 2922, 2852, 1748, 1643, 1603, 1510, 1454,
1325, 1223, 1191, 1133, 949, 834, 747, 698, 505; ESI–MS m/z (%): 376 ([M - H]-,
100.0); Anal. Calcd for C17H13BrFNO3: C 53.99, H 3.45, N 3.70, Found: C 53.78, H
3.37, N 3.84.
5-Benzyloxy-3-bromo-4-(4-chlorophenyl)aminofuran-2(5H)-one (3p)
White solid, yield 31 %; m.p. 109.1–110.3 °C; UV–visible (CH2Cl2) kmax: 292 nm;
1H NMR (400 MHz, CDCl3-TMS) d: 4.54–4.77 (2H, dd, J1 = 12.0 Hz,
J2 = 12.0 Hz, CH2-6), 5.97 (1H, s, CH-5), 6.69 (1H, s, NH-7), 7.00–7.08 (4H, m,
ArH-9, 10, 12, 13), 7.26–7.36 (5H, m, ArH-15, 16, 17, 18, 19); 13C NMR
(100 MHz, CDCl3-TMS) d: 71.2, 80.2, 96.6, 125.0, 128.6, 128.7, 128.8, 129.5,
132.0, 134.7, 135.2, 157.1, 167.1; IR (film) m: 3266, 3060, 3034, 2926, 2852, 1748,
1642, 1593, 1493, 1455, 1325, 1191, 1128, 1014, 822, 746, 698, 672, 507; ESI–MS
m/z (%): 392 ([M - H]-, 74.9); Anal. Calcd for C17H13BrClNO3: C 51.74, H 3.32,
N 3.55, Found: C 51.59, H 3.50, N 3.49.
5-Benzyloxy-3-bromo-4-(4-bromophenyl)aminofuran-2(5H)-one (3q)
Yellow solid, yield 21 %; m.p. 102.9–103.6 °C; UV–visible (CH2Cl2) kmax
:
1
292 nm; H NMR (400 MHz, CDCl3-TMS) d: 4.55–4.77 (2H, dd, J1 = 12.0 Hz,
J2 = 12.0 Hz, CH2-6), 5.98 (1H, s, CH-5), 6.67 (1H, s, NH-7), 6.95 (2H, d,
J = 8.0 Hz, ArH-9, 13), 7.05 (2H, d, J = 8.0 Hz, ArH-10, 12), 7.30–7.37 (3H, m,
ArH-16, 17, 18), 7.42 (2H, d, J = 8.0 Hz, ArH-15, 19); 13C NMR (100 MHz,
CDCl3-TMS) d: 71.2, 80.4, 96.6, 119.7, 125.1, 128.7, 128.7, 128.8, 132.5, 134.7,
135.8, 157.0, 167.0; IR (film) m: 3265, 3027, 2924, 2853, 1748, 1641, 1587, 1528,
1490, 1454, 1323, 1190, 1128, 1011, 817, 746, 698, 498; ESI–MS m/z (%): 436
([M - H]-, 49.7); Anal. Calcd for C17H13Br2NO3: C 46.50, H 2.98, N 3.19, Found:
C 46.39, H 3.04, N 3.38.
123

1166
F.-L. Xue et al.
5-Benzyloxy-3-bromo-4-(3-chlorophenyl)aminofuran-2(5H)-one (3r)
Yellow solid, yield 26 %; m.p. 118.0–119.2 °C; UV–visible (CH2Cl2) kmax
:
1
289 nm; H NMR (400 MHz, CDCl3-TMS) d: 4.57–4.81 (2H, dd, J1 = 12.0 Hz,
J2 = 12.0 Hz, CH2-6), 6.02 (1H, s, CH-5), 6.62 (1H, s, NH-7), 6.98 (1H, d,
J = 8.0 Hz, ArH-9), 7.07–7.12 (2H, m, ArH-10, 11), 7.14 (1H, s, ArH-13),
7.21–7.26 (2H, m, ArH-16, 18), 7.29–7.34 (3H, m, ArH-15, 17, 19); 13C NMR
(100 MHz, CDCl3-TMS) d: 71.3, 81.1, 96.8, 121.3, 123.4, 126.4, 128.7, 128.7,
128.7, 130.4, 134.7, 135.1, 137.9, 156.7, 166.8; IR (film) m: 3352, 3060, 3033, 2922,
2851, 1748, 1638, 1592, 1534, 1479, 1322, 1191, 1127, 951, 746, 698, 505; ESI–MS
m/z (%): 392 ([M - H]-, 80.0); Anal. Calcd for C17H13BrClNO3: C 51.74, H 3.32,
N 3.55, Found: C 51.54, H 3.52, N 3.39.
5-Benzyloxy-3-bromo-4-(naphthalen-1-ylamino)furan-2(5H)-one (3s)
Brown solid, yield 22 %; m.p. 51.6–53.2 °C; UV–visible (CH2Cl2) kmax: 294 nm;
1H NMR (400 MHz, CDCl3-TMS) d: 4.27–4.62 (2H, dd, J1 = 12.0 Hz,
J2 = 12.0 Hz, CH2O-6), 5.83 (1H, s, CH-5), 6.68 (1H, d, J = 8.0 Hz, ArH-9),
6.75 (1H, s, NH-7), 7.08–7.14 (2H, m, ArH-16, 18), 7.18–7.22 (1H, m, ArH-10),
7.33–7.45 (3H, m, ArH-15, 17, 19), 7.55–7.61 (2H, m, ArH-22, 23), 7.88 (1H, d,
J = 8.0 Hz, Ar–H-11), 7.91–7.96 (2H, m, Ar–H-20, 21); 13C NMR (100 MHz,
CDCl3-TMS) d: 71.2, 79.1, 96.8, 121.9, 123.9, 125.3, 126.9, 127.4, 128.3, 128.4,
128.4, 128.6, 129.9, 132.4, 134.2, 134.7, 158.9, 167.2; IR (film) m: 3359, 3032.9,
2922, 2852, 1763, 1640, 1575, 1506, 1470, 1331, 1209, 1122, 954, 774, 747, 697,
514; ESI–MS m/z (%): 408 ([M - H]-, 100.0); Anal. Calcd for C21H16BrNO3: C
61.48, H 3.93, N 3.41, Found: C 61.65, H 4.10, N 3.37.
5-Benzyloxy-3-bromo-4-(4-methylbenzyl)aminofuran-2(5H)-one (3t)
White solid, yield 78 %; m.p. 125.9–126.2 °C; UV–visible (CH2Cl2) kmax: 276 nm;
1H NMR (400 MHz, CDCl3-TMS) d: 2.34 (3H, s, CH3-21), 4.48 (2H, s, CH2-8),
4.64–4.82 (2H, dd, J1 = 12.0 Hz, J2 = 12.0 Hz, CH2O-6), 5.42 (1H, s, NH-7), 5.76
(1H, s, CH-5), 7.09 (2H, d, J = 8.0 Hz, ArH-10, 14), 7.15 (2H, d, J = 8.0 Hz, ArH-
11, 13), 7.28–7.38 (5H, m, ArH-15, 16, 17, 18, 19); 13C NMR (100 MHz, CDCl3-
TMS) d: 21.2, 47.4, 70.4, 77.3, 96.3, 127.4, 128.7, 128.7, 129.7, 133.7, 135.3, 138.1,
159.8, 167.6; IR (film) m: 3300, 3027, 2921, 2851, 1747, 1637, 1547, 1514, 1495,
1451, 1322, 1215, 1122, 923, 801, 745, 697, 502; ESI–MS m/z (%): 410
([M ? Na]?, 100.0); Anal. Calcd for C19H18BrNO3: C 58.78, H 4.67, N 3.61,
Found: C 58.75, H 4.72, N 3.42.
5-Benzyloxy-3-bromo-4-(4-methoxybenzyl)aminofuran-2(5H)-one (3u)
White solid, yield 83 %; m.p. 107.4–108.6 °C; UV–visible (CH2Cl2) kmax: 276 nm;
1H NMR (400 MHz, CDCl3-TMS) d: 3.78 (3H, s, CH3O-21), 4.46 (2H, s, CH2-8),
4.64 * 4.81 (2H, dd, J1 = 12.0 Hz, J2 = 12.0 Hz, CH2O-6), 5.44 (1H, s, NH-7),
5.77 (1H, s, CH-5), 6.86 (2H, d, J = 8.0 Hz, ArH-11, 13), 7.13 (2H, d, J = 8.0 Hz,
123

Synthesis of 5-alkoxy-4-amino-3-bromo-2(5H)-furanone
1167
ArH-10, 14), 7.29–7.39 (5H, m, ArH-15, 16, 17, 18, 19); 13C NMR (100 MHz,
CDCl3-TMS) d: 47.1, 55.4, 70.4, 77.3, 96.4, 114.3, 128.5, 128.6, 128.7, 128.9,
129.3, 135.0, 159.5, 167.7; IR (film) m: 3357, 3066, 3027, 2922, 2851, 1748, 1639,
1586, 1513, 1455, 1322, 1249, 1176, 1126, 937, 818, 745, 698, 595; ESI–MS m/
z (%): 426 ([M ? Na]?, 100.0); Anal. Calcd for C19H18BrNO4: C 56.45, H 4.49, N
3.46, Found: C 56.38, H 4.70, N 3.27.
5-Benzyloxy-3-bromo-4-(2-chlorobenzyl)aminofuran-2(5H)-one (3v)
Yellowish solid, yield 64 %; m.p. 46.7–47.9 °C; UV–visible (CH2Cl2) kmax
:
274 nm; 1H NMR (400 MHz, CDCl3-TMS) d: 4.59 (2H, s, CH2-8), 4.66–4.81 (2H,
dd, J1 = 12.0 Hz, J2 = 12.0 Hz, CH2O-6), 5.67 (1H, s, NH-7), 5.81 (1H, s, CH-5),
7.16–7.25 (3H, m, ArH-12, 13, 14), 7.29–7.36 (5H, m, ArH-15, 16, 17, 18, 19), 7.38
(1H, d, J = 8.0 Hz, ArH-11); 13C NMR (100 MHz, CDCl3-TMS) d: 45.5, 70.5,
77.3, 96.3, 126.2, 127.4, 128.7, 128.8, 129.0, 129.6, 129.9, 133.1, 134.5, 135.2, 159,
167.5,; IR (film) m: 3314, 3067, 3027, 2922, 2852, 1749, 1643, 1574, 1528, 1444,
1324, 1217, 1131, 947, 747,699, 524; ESI–MS m/z (%): 408 ([M ? H]?, 8.5), 430
([M ? Na]?, 68.7); Anal. Calcd for C18H15BrClNO3: C 52.90, H 3.70, N 3.43,
Found: C 52.78, H 3.66, N 3.60.
4-Benzylamino-5-benzyloxy-3-bromofuran-2(5H)-one (3w)
Yellow solid, yield 76 %; m.p. 78.4–79.3 °C; UV–visible (CH2Cl2) kmax: 275 nm;
1H NMR (400 MHz, CDCl3-TMS) d: 4.53 (2H, s, CH2-8), 4.64–4.82 (2H, dd,
J1 = 12.0 Hz, J2 = 12.0 Hz, CH2O-6), 5.47 (1H, s, NH-7), 5.76 (1H, s, CH-5), 7.21
(2H, d, J = 8.0 Hz, ArH-10, 14), 7.29–7.37 (8H, m, ArH-11, 12, 13, 15, 16, 17, 18,
19); 13C NMR (100 MHz, CDCl3-TMS) d: 47.5, 70.5, 77.3, 96.3, 127.4, 128.2,
128.7, 128.8, 129.0, 135.3, 136.8, 159.6, 167.5; IR (film) m: 3359, 3060, 3027, 2921,
2851, 1748, 1638, 1531, 1495, 1455, 1322, 1215, 1120, 933, 746, 697, 573; ESI–MS
m/z (%): 374 ([M ? H]?, 8.5), 396 ([M ? Na]?, 87.4); Anal. Calcd for
C18H16BrNO3: C 57.77, H 4.31, N 3.74, Found: C 57.89, H 4.38, N 3.85.
Acknowledgments The authors’ are grateful to the National Natural Science Foundation of China
(no. 20772035), the Third Talents Special Funds of Guangdong Higher Education (no. Guangdong-Finance-
Education [2011]431) and the Natural Science Foundation of Guangdong Province (no. S2011010001556)
for financial support.
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