The new convenient synthesis of novel γ-alkylidenebutenolides from 6-aminopenicillanic acid

Article abstract of DOI:10.3987/COM-12-12611

Butenolides have good biological activity and serve as the important unit of pharmaceutical intermediates, of which γ-alkylidenebutenolides have gained wide attention over the last past decades particularly. A simple and practical method for the synthesis of butenolide 6 and its 5-substituted analogues 7a-t via vinylogous aldol reaction from 6-aminopenicillanic acid (6-APA) with the ratio of Z/E isomers between 1.1/1.0 and 1.0/0 under mild conditions in 6 steps was first reported. Besides, we also reported the methanolysis behaviors of azetidinone fused oxazoline derivatives. All the synthesized γ-alkylidenebutenolides are new and are currently being evaluated for their biological activities.

Full text of DOI:10.3987/COM-12-12611

HETEROCYCLES, Vol. 87, No. 1, 2013
163
HETEROCYCLES, Vol. 87, No. 1, 2013, pp. 163 - 176. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 26th October, 2012, Accepted, 15th November, 2012, Published online, 22nd November, 2012
DOI: 10.3987/COM-12-12611
THE
NEW
CONVENIENT
SYNTHESIS
OF
NOVEL
γ-ALKYLIDENEBUTENOLIDES FROM 6-AMINOPENICILLANIC ACID
Bin Yu,a En Zhang,a Yuan Fang,a Xiao-nan Sun,a Jing-li Ren,a De-quan
Yu,b* and Hong-min Liua*
a School of Pharmaceutical Sciences and New Drug Research & Development
Centre, Zhengzhou University, Zhengzhou 450001, P. R. China. E-mail:
liuhm@zzu.edu.cn
b
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking
Union Medical College, Beijing 100050, P. R. China. E-mail: dqyu@imm.ac.cn
Abstract – Butenolides have good biological activity and serve as the important
unit of pharmaceutical intermediates, of which γ-alkylidenebutenolides have
gained wide attention over the last past decades particularly. A simple and practical
method for the synthesis of butenolide 6 and its 5-substituted analogues 7a-t via
vinylogous aldol reaction from 6-aminopenicillanic acid (6-APA) with the ratio of
Z/E isomers between 1.1/1.0 and 1.0/0 under mild conditions in 6 steps was first
reported. Besides, we also reported the methanolysis behaviors of azetidinone
fused oxazoline derivatives. All the synthesized γ-alkylidenebutenolides are new
and are currently being evaluated for their biological activities.
Due to their large abundance and their biological interest and potential medicinal value, butenolides have
been extensively studied. Many natural products, including prominent compounds such as freelingyne,1
rubrolides,2 tetrenolin3 (Figure 1), belong to the pharmacologically important group of
γ-alkylidenebutenolides (γ-AIBs), which have gained an increasing amount of attention over the last past
decades.4 Most of them exhibit various interesting biological activities, such as antibacterial, anticancer,
antibiotic and so on.5 For example, freelingyne displays antibiotic activity6 and rubrolides, which are
marine tunicate metabolites, exhibit potent antibiotic activities in vitro.5b Principally, the efficient
synthetic strategies towards the γ-AIBs mainly focus on five major respects, which were reviewed
comprehensively by Rao,7 Negishi,8 Bruckner,9 and Langer.10 Many efforts have been dedicated to seek
highly potent γ-AIBs on their pharmacological activities.

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HETEROCYCLES, Vol. 87, No. 1, 2013
Figure 1. Some naturally occurring γ-AIBs
Our previous work indentified that γ-AIBs based derivatives showed moderate to excellent biological
activities, such as antitumor activity,11 α-glucosidase inhibitory activity,12 and antagonist of histamine.13
Besides, γ-AIBs could regulate the intercellular Na+ concentration.14 As part of our ongoing effort to
indentify new biological agents, we are interested in investigating novel γ-AIBs, expecting to find lead
structures for further preclinical research. Herein we report an efficient route to access the novel γ-AIBs
with a similar amino acid side chain starting from commercially available 6-aminopenicillanic acid
(6-APA) (Scheme 1).
Ph
Ph
O
S
H
H
H
H
N
O
N
O
BzHN
S
H2N
a
b
c
H
H
H
H
N
N
N
N
Cl
O
O
O
O
CO2CHPh2
CO2H
1, 6-APA
CO2CHPh2
CO2CHPh2
2
4
3
O
O
O
O
O
O
O
O
O
O
O
H
H
H
N
CO2CHPh2
Cl
N
N
N
H
d
e
N
H
N
H
f
O
O
O
O
O
R1
R2
7
5
6
Scheme 1. Reagents and conditions: (a) (i) BzCl, aqueous Na2CO3, 0 oC; (ii) MeCO3H, DCM, 0 oC; (iii)
o
benzophenone hydrazone, MeCO3H, DCM, 0 C; (b) PPh3, squaric acid, toluene/DMA, reflux; (c) (i)
Cl2/CCl4, EtOAc, rt; (ii) aqueous Na2SO3, NaHCO3, rt; (d) MeOH, rt; (e) Na2CO3, MeCN/H2O, reflux; (f)
Aldehydes, Na2CO3, MeOH, reflux or ketones, 1,2-ethanediamine, MeOH, reflux.
Initially, penicillin sulfoxide 2 was prepared from commercially available 6-APA in one-pot procedure.
Acylation of 6-APA, oxidation, followed by protection of carboxyl group to give compound 2 in 89%
yield in ice bath, When the reaction temperature increased to room temperature, it gave a complex
mixture due to the instability of β-lactam ring. Oxazoline 3 was successfully synthesized from penicillin
sulfoxide 2 in 85% yield. As reported by Yamamoto et al.,15 acid was necessary for formation of 3. After
screening the acids, such as benzoic acid, formic acid, niacin, and squaric acid, we found that a catalytic
amount of squaric acid (0.05 eq) was efficient for the formation of oxazoline 3 due to its low pk1 value

HETEROCYCLES, Vol. 87, No. 1, 2013
165
and little nucleophilicity. N,N-Dimethylacetamide (DMA), as a co-solvent, was found essential and an
optimal amount of DMA was 5-10% of the solvent. Excess amount of DMA caused double-bond
isomerization at the butenoate side chain, which was in agreement with the literature report.15 The allylic
chlorination of oxazoline 3 by simple addition of chlorine, followed by treatment with aqueous sodium
hydrogen carbonate proceeded well and gave allylic chloride 4 in 75% yield via an ene-type reaction
mechanism.16
As part of our continuing efforts to find an efficient method for synthesizing the oxacephem derivatives,
we found that treatment of 4 with methanol gave an unexpected dipeptide 5 in high yield without any
catalyst at room temperature due to the formation of the unstable 4-methoxyl-azetidin-2-one intermediate
leading to a non-lactam dipeptide 5 under the same reaction condition, which was similar to Kamata’s
report (Scheme 2).17 To the best of our knowledge, this is the first report about the methanolysis of
azetidinone fused oxazoline derivatives.
Scheme 2. The plausible mechanism of methanolysis of azetidinone fused oxazoline derivatives
Inspired by this interesting finding, we further explored the effects of the substituents on the methanolysis
of azetidinone fused oxazoline derivatives (Table 1). When R1=Ph and R2=H (Table 1, entry 1), the
structure remained unchanged in methanol even under reflux. In comparison, when R1=Bn and R2=H
(Table 1, entry 2), it caused the cleavage of the C-N bond affording the oxazole derivate 5a at room
temperature. To our surprise, when R1=Ph and R2=Cl (Table 1, entry 3), an unexpected dipeptide 5 was
efficiently obtained in good yield (75%). The detailed mechanism towards these different behaviors
remains unclear.
Table 1. The effects of the substituents on the methanolysis of azetidinone fused oxazoline derivatives
Entry
R1 a
R2
Reaction Conditions
Products
1
Ph
H
MeOH, reflux

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HETEROCYCLES, Vol. 87, No. 1, 2013
2
Bn
Ph
H
MeOH, rt ~ reflux
3b
Cl
MeOH, rt
a Ph=phenyl; Bn=benzyl; b Compound 5 was characterized by 1D and 2D NMR spectra.
Base-catalyzed intramolecular cascade sequence afforded the butenolide 6, which involved three cascade
reactions: (a) substitution reaction of the chloride with hydroxide anion; (b) the intramolecular
transesterification; (c) base promoted isomerization of double bond (Scheme 3).
Scheme 3. The base catalyzed intramolecular cascade sequence
In order to obtain good yield of compound 6, we examined the reaction under various conditions (solvent,
base, temperature, and phase transfer catalyst). The results were summarized in Table 2. We found that
solvents and bases played an important role in this reaction sequence, while TBAB was not necessary for
this reaction. When the reaction was performed in MeCN/H2O (4/1) (Table 2, entry 1), compound 6 was
obtained in 78% yield. When the amount of water used decreased, the yield was only 5% and 60% with
prolonged time (>12 h), respectively (Table 2, entries 2, 4). When 1.0 eq of TBAB was added, the yield
remained almost unchanged (Table 2, entry 3). When the mild base NaHCO3 was used, the yield was
42% (Table 2, entry 7). Compound 5 was completely decomposed due to the strong basicity of NaOH and

HETEROCYCLES, Vol. 87, No. 1, 2013
167
no product was obtained (Table 2, entry 8). When DMF/H2O (4/1) as the solvent was used, the yield
decreased to about 30% (Table 2, entry 5). Particularly, when MeOH/H2O (4/1) was used as the solvent
(Table 2, entry 6), it caused the isomerization of double bond; no desired product 6 was observed. Thus,
the best condition for this reaction was the use of compound 5 (1.0 eq), Na2CO3 (1.0 eq), MeCN/H2O
(4/1) as the solvent under reflux (Table 2, entry 1).
Table 2. Screening of the reaction conditions
Entry
1
Basea
TBAB
---b
Temperature
82 ºC
Solvent (V/V)
Yieldsc
78%
Na2CO3
MeCN/H2O(4/1)
2
3
4
5
6
7
8
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaHCO3
NaOH
---
1.0 eq
---
82 ºC
82 ºC
82 ºC
100 ºC
65 ºC
82 ºC
82 ºC
MeCN
5%
MeCN/H2O(4/1)
MeCN/H2O(40/1)
DMF/H2O(4/1)
MeOH/H2O(4/1)
MeCN/H2O(4/1)
MeCN/H2O(4/1)
77%
60%
---
30%
---
0
---
42%
---
complex mixture
a 1.0 eq of base was used; b --- means no TBAB was added; c recrystallized from EtOH.
Our group previously developed an efficient method for the construction of γ-AIBs, which was
successfully applied to the stereoselective synthesis of andrographolide and digoxin derivatives
containing γ-AIB moiety.18 Our strategy involved the investigation of the effects of bases (pyridine,
1,2-ethanediamine, DMAP, NaHCO3, Na2CO3 and K2CO3) and solvents (CHCl3, MeCN, THF and
MeOH) in the aldol condensation of butenolide with aldehydes or ketones, revealing that Na2CO3 proved
to be more effect in promoting the aldol condensation with most of aldehydes, but to ketones, the catalyst
1,2-ethanediamine was the most effective in methanol. Unfortunately, no desired products were obtained
under this protocol when compound 6 was subjected to aromatic ketones and aliphatic aldehydes due to
the low reactivity of them. Besides, we also found that treatment 6 with aromatic aldehydes with
electron-withdrawing group did not afford the corresponding products, showing that the electronic effect
of the substituents on the aromatic ring had a remarkable effect on this reaction.

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HETEROCYCLES, Vol. 87, No. 1, 2013
Having established the optimal conditions, we then applied the protocol to the vinylogous aldol reaction
of different aldehydes or ketones with 6, affording a series of novel γ-alkylidenebutenolides (7a-t) in
53%-86% yields (Table 3). Besides, different ratio of Z- or E-isomer was observed depending on the R1
and R2 groups which could be explained by an E1cb mechanism19 whereby the formation of the Z-isomer
was favored due to the steric hindrance provided by the β-methyl (Scheme 4). The Z-isomers are
generally more stable than their E-counterparts, especially when a β-substituent exists.20 That is why most
naturally occurring γ-alkylidenebutenolides have the Z-configuration, although many of them lack a
β-substituent, as represented by freelingyne and tetrenolin (Figure 1).
R
R
R
HO
O
O
O
HO
O
O
O
H
Ar
base
syn
Ar
Ar
Z
R
R
R
O
HO
O
Ar
Ar
O
O
O
O
H
Ar
base
OH
anti
E
Scheme 4. E1cb mechanism for the formation of Z-isomers
Table 3. Reactions of compound 6 with aldehydes and ketonesa
Compound
R1
Me
Me
R2
Me
Et
Time (h)
Yieldsb (%) (Z/E)
65
7a
7b
5
5
60 (1.1/1.0)
7c
7d
7e
5
3
3
63
O
H
H
75 (5.7/1.0)
79 (1.0/0)

HETEROCYCLES, Vol. 87, No. 1, 2013
169
7f
H
H
3
4
86 (4.6/1.0)
81 (7.7/1.0)
7g
7h
H
4
70 (7.8/1.0)
7i
7j
H
H
H
H
H
4
4
5
5
5
84 (1.8/1.0)
78 (12.9/1.0)
53 (6.4/1.0)
65 (1.5/1.0)
61 (1.7/1.0)
7k
7l
7m
7n
7o
7p
H
H
H
3
4
6
78 (22.6/1.0)
72 (1.0/0)
N
74 (10.2/1.0)
N
7q
7r
H
H
6
6
72 (1.0/0)
Cl
N
68 (4.8/1.0)
F
7s
7t
H
H
6
6
80 (2.1/1.0)
82 (4.6/1.0)
a
Reagents and conditions: MeOH, Na2CO3 or 1,2-ethanediamine, compound 6: aldehydes or ketones =
1:1.05, reflux. b Isolated yields.

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HETEROCYCLES, Vol. 87, No. 1, 2013
In summary, we have developed a simple method to synthesize a series of novel γ-alkylidenebutenolides
from readily available starting material 6-APA. Besides, we first reported the methanolysis behaviors of
azetidinone fused oxazoline derivatives under mild condition and the detailed mechanism is under
investigation. Butenolide 6 was synthesized via the intramolecular cascade sequence in one-pot under
mild condition. This strategy is valuable for the construction of compound libraries and the screening of
lead compound. Efforts towards biological evaluation of these new compounds are in progress and will be
reported elsewhere.
EXPERIMENTAL
All reagents and solvents used were of analytical grade purchased from commercial sources. Thin-layer
chromatography (TLC) was carried out on glass plates coated with silica gel (Qingdao Haiyang Chemical
Co., G60F-254) and visualized by UV light (254 nm). The products were purified by column
chromatography over silica gel (Qingdao Haiyang Chemical Co., 200–300 mesh). Melting points were
determined on a Beijing Keyi XT4A apparatus and are uncorrected. All NMR spectra were recorded with
a Bruker DPX 400 MHz spectrometer with TMS as internal standard. Chemical shifts are given as δ ppm
values relative to TMS. Mass spectra (MS) were recorded on Esquire3000 mass spectrometer by
electrospray ionization (ESI).
Synthesis of compound 4 Compound 4 was prepared from 6-APA according to the literature
procedures.15,16 Compound 4 was synthesized from 6-APA by acylation, oxidation and protection of
carboxyl group in one pot to give penicillin sulfoxide 2, which was subjected to rearrangement and
chlorination with an overall yield of about 56.7%. White solid; 1H NMR (400 MHz, CDCl3, TMS) δ 7.90
(d, J = 7.3 Hz, 2H), 7.59–7.27 (m, 13H), 6.92 (s, 1H,), 6.30 (d, J = 3.3 Hz, 1H), 5.47 (s, 1H), 5.37 (d, J =
13
3.3 Hz, 1H), 5.28 (s, 1H), 5.12 (s, 1H), 4.13–3.99 (dd, J = 12.0, 16.0 Hz, 2H); C NMR (101 MHz,
CDCl3, TMS) δ 167.70, 166.80, 166.76, 138.94, 138.88, 138.26, 132.34, 128.62, 128.38, 127.26, 127.02,
126.84, 120.49, 86.25, 82.14, 79.09, 77.38, 77.06, 76.74, 55.09, 45.60.
Synthesis of dipeptide 5 Compound 4 (10 mmol) was placed in a flask and MeOH (20 mL) was added,
the reaction mixture was stirred overnight at room temperature. The product was precipitated gradually
from the solution, filtered and dried as a white solid; Yield: 75%; mp 136.1-136.6 ºC; 1H NMR (400 MHz,
CDCl3, TMS) δ 7.87–7.80 (d, 2H), 7.62 (d, J = 7.5 Hz, 1H), 7.58–7.22 (m, 14H), 6.90 (s, 1H), 5.47 (s,
1H), 5.43 (s, 1H), 5.36 (d, J = 7.5 Hz, 1H), 4.80 (dd, J = 6.0, 2.2 Hz, 1H), 4.77 (d, J = 2.2 Hz, 1H), 4.14
13
(dd, J = 42.1, 12.4 Hz, 2H), 3.59 (s, 3H), 3.45 (s, 3H); C NMR (101 MHz, CDCl3, TMS) δ 168.64,
167.33, 167.22, 140.10, 139.27, 139.23, 133.56, 132.05, 128.73, 128.65, 128.38, 128.31, 127.26, 127.20,
127.15, 119.52, 104.87, 78.96, 57.78, 56.85, 55.74, 55.56, 44.94; HRMS (ESI): m/z calcd for
C30H32ClN2O6 (M+H)+, 551.1949; found, 551.1945.

HETEROCYCLES, Vol. 87, No. 1, 2013
171
Synthesis of butenolide 6 To a solution of 5 (9 mmol) in MeCN/H2O (4/1, 20 mL) was added Na2CO3 (9
mmol), the resulting mixture was stirred under reflux for about 4 h. The reaction mixture was evaporated
in vacuum when completed and then EtOAc and water were added, the aqueous layer was extracted with
EtOAc, the combined organic layers were washed with water and brine, dried and concentrated
successively. The residue was subjected to recrystallization from EtOH to give 6 as a white solid; Yield:
78%; mp 146.3-147.6 ºC; 1H NMR (400 MHz, CDCl3, TMS) δ 8.28 (s, 1H), 7.94–7.41 (m, 5H), 7.18 (d, J
= 6.3 Hz, 1H), 4.93 (dd, J = 6.3, 2.7 Hz, 1H), 4.80 (d, J = 2.7 Hz, 1H), 4.73 (s, 2H), 3.63 (s, 3H), 3.50 (s,
3H), 2.18 (s, 3H); 13C NMR (101 MHz, CDCl3, TMS) δ 170.62, 167.41, 166.42, 145.69, 133.35, 132.10,
128.69, 127.24, 120.90, 104.34, 72.13, 57.57, 56.54, 55.97, 14.07; HRMS (ESI): m/z calcd for
C17H20N2NaO6 (M+Na)+, 371.1219; found, 371.1216.
General procedure for preparation of compounds 7a-t To a solution of 6 (1 mmol) in MeOH (10 mL)
was added Na2CO3 (1 mmol), the resulting mixture was stirred under reflux for about 3 h, MeOH was
removed and water was added. The mixture was extracted with EtOAc. The combined organic layers
were washed with water, brine, dried (Na2SO4), concentrated, and then purified by column
chromatography on silica gel (Petroleum ether /EtOAc = 2/1).
3-Substituted amino-4-methyl-5-(propan-2-ylidene) furan-2(5H)-one (7a) White solid; Yield: 65%;
mp 135.6-136.3 ºC; 1H NMR (400 MHz, CDCl3, TMS) δ 8.13 (s, 1H), 7.87 (d, J = 7.8 Hz, 2H), 7.45-7.55
(m, 3H), 7.20 (d, J = 6.3 Hz, 1H), 4.94 (dd, J = 6.3, 2.5 Hz, 1H), 4.81 (d, J = 2.5 Hz, 1H), 3.63 (s, 3H),
3.50 (s, 3H), 2.25 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H); 13C NMR (101 MHz, CDCl3, TMS) δ 167.43, 166.67,
165.70, 143.79, 140.63, 133.34, 132.10, 128.69, 127.25, 124.19, 122.86, 104.39, 57.44, 56.65, 56.07,
20.74, 18.91, 15.43. HRMS (ESI): m/z calcd for C20H25N2O6 (M+H)+, 389.1713; found, 389.1718.
3-Substituted amino-5-(butan-2-ylidene)-4-methylfuran-2(5H)-one (7b) White solid; Yield: 60%; mp
97.9-98.7 ºC; 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.90–7.83 (m, 2H), 7.58–7.42 (m, 3H), 7.21 (d,
J = 6.4 Hz, 1H), 4.94 (dd, J = 6.4, 2.7 Hz, 1H), 4.81 (d, J = 2.7 Hz, 1H), 3.62 (s, 3H), 3.49 (s, 3H), 2.42 (q,
J = 7.5 Hz, 2H), 2.25 (s, 3H), 2.05 and 2.02 (two singlets, 3H), 1.16-1.06 (m, 3H); 13C NMR (101 MHz,
CDCl3) δ 167.44, 166.71, 165.71, 143.53, 143.34, 140.83, 140.42, 133.35, 132.09, 130.17, 129.70, 128.68,
127.25, 104.39, 57.40, 56.61, 56.07, 29.71, 27.38, 25.33, 17.93, 16.54, 15.46, 14.89, 13.07, 12.28; HRMS
(ESI): m/z calcd for C21H27N2O6 (M+H)+, 403.1869; found, 403.1868.
3-Substituted amino-5-cyclohexylidene-4-methylfuran-2(5H)-one (7c) White solid; Yield: 63%; mp
128.3-129.5 ºC; 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.93–7.82 (m, 2H), 7.45-7.57 (m, 3H), 7.21
(d, J = 6.4 Hz, 1H), 4.94 (dd, J = 6.4, 2.7 Hz, 1H), 4.81 (d, J = 2.7 Hz, 1H), 3.63 (s, 3H), 3.49 (s, 3H),
2.62–2.46 (t, 4H), 2.25 (s, 3H), 1.66 (d, J = 6.3 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 167.44, 166.74,
165.73, 141.22, 140.77, 133.36, 133.00, 132.09, 128.69, 127.25, 123.46, 104.39, 57.39, 56.63, 56.08,
29.91, 28.07, 27.60, 26.15, 15.59; HRMS (ESI): m/z calcd for C23H29N2O6 (M+H)+, 429.2026; found,

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HETEROCYCLES, Vol. 87, No. 1, 2013
429.2025.
3-Substituted amino-5-(furan-2-ylmethylene)-4-methylfuran-2(5H)-one (7d) Yellow solid; Yield:
75%; mp 82.1-82.8 ºC;1H NMR (400 MHz, CDCl3, TMS) δ 8.45 (s, 1H), 7.89-7.83 (m, 2H), 7.46-7.55 (m,
3H), 7.46 (s, 1H), 7.21 (d, J = 6.4 Hz, 1H), 6.99 (t, J = 3.2 Hz, 1H), 6.53 (d, J = 1.5 Hz, 1H), 6.17 (s, 1H),
4.96 (dd, J = 6.4, 2.5 Hz, 1H), 4.81 (d, J = 2.5 Hz, 1H), 3.65 (s, 3H), 3.51 (s, 3H), 2.24 (s, 3H); 13C NMR
(101 MHz, CDCl3, TMS) δ 167.43 , 166.34 , 165.72 , 149.04 , 146.15 , 143.67 , 137.27 , 133.29 , 132.15 ,
128.71 , 128.57 , 127.25 , 121.57 , 114.45 , 112.94 , 104.36 , 99.04 , 57.65 , 56.62 , 56.10 , 11.62; HRMS
(ESI): m/z calcd for C22H22N2NaO7 (M+Na)+, 449.1325; found, 449.1326.
5-((1H-Pyrrol-2-yl)methylene)-3-substituted amino-4-methylfuran-2(5H)-one (7e) Yellow solid;
Yield: 79%; mp 151.3-151.6 ºC; 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 10.03 (s, 1H), 8.64 (t, J
= 8.5 Hz, 1H), 7.91 (m, 2H), 7.53 (m, 3H), 7.01 (d, J = 1.2 Hz, 1H), 6.61 (s, 1H), 6.39 (s, 1H), 6.22 (dd, J
= 5.6, 2.4 Hz, 1H), 5.02–4.90 (m, 1H), 4.78 (d, J = 7.2 Hz, 1H), 3.38 (s, 3H), 3.37 (s, 3H), 2.04 (s, 3H);
13C NMR (101 MHz, DMSO-d6) δ 168.52, 166.65, 165.75, 143.29, 142.91, 134.21, 132.00, 128.75,
128.06, 126.12, 123.48, 120.66, 114.83, 110.91, 103.20, 102.32, 55.46, 55.39, 53.83, 10.71; HRMS
(ESI): m/z calcd for C22H24N3O6 (M+H)+, 426.1665; found, 426.1667.
3-Substituted amino-4-methyl-5-((5-methylfuran-2-yl)methylene)furan-2(5H)-one (7f) Yellow solid;
1
Yield: 86%; mp 151.3-151.6 ºC; H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.86 (m, J = 16.1, 7.6 Hz,
2H), 7.62–7.40 (m, 4H), 7.20 (d, J = 6.3 Hz, 1H), 6.89 (s, 1H), 6.14 (d, J = 2.6 Hz, 1H), 4.96 (dd, J = 6.3,
2.4 Hz, 1H), 4.81 (d, J = 2.4 Hz, 1H), 3.64 (s, 3H), 3.50 (s, 3H), 2.35 (s, 3H), 2.22 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 167.45, 166.33, 165.87, 154.25, 147.59, 145.07, 137.70, 133.33, 132.12, 128.70, 127.25,
120.99, 116.13, 109.60, 104.37, 99.37, 57.59, 56.59, 56.10, 13.84, 11.52; HRMS (ESI): m/z calcd for
C23H24N2NaO7 (M+Na)+, 463.1481; found, 463.1487.
3-Substituted amino-4-methyl-5-(3,4,5-trimethoxybenzylidene)furan-2(5H)-one (7g) Yellow solid;
1
Yield: 81%; mp 153.5-155.8 ºC; H NMR (400 MHz, CDCl3, TMS) δ 8.45 (s, 1H), 7.93–7.87 (m, 2H),
7.60–7.41 (m, 3H), 7.21 (d, J = 6.4 Hz), 7.02 (s, 2H), 6.05 (s, 1H), 4.98 (dd, J = 6.4, 2.7 Hz, 1H), 4.82 (d,
J = 2.7 Hz, 1H), 3.91 (s, 6H), 3.89 (s, 3H), 3.65 (s, 3H), 3.51 (s, 3H), 2.28 (s, 3H); 13C NMR (101 MHz,
CDCl3, TMS) δ 167.46, 166.45, 166.04, 153.27, 147.38, 138.97, 138.53, 133.29, 132.17, 128.72, 128.64,
128.51, 127.25, 121.34, 110.15, 107.67, 104.34, 61.00, 57.66, 56.56, 56.21, 56.13, 11.83; HRMS (ESI):
m/z calcd for C26H27N2O6 (M+H)+, 463.1869; found, 463.1866.
3-Substituted amino-4-methyl-5-((E)-3-phenylallylidene)furan-2(5H)-one (7h) Yellow solid; Yield:
1
70%; mp 124.6-124.8 ºC; H NMR (400 MHz, CDCl3, TMS) δ 8.47 (s, 1H), 7.86–7.93 (m, 2H),
7.41–7.60 (m, 5H), 7.26–7.42 (m, 4H), 7.20 (d, J = 6.4 Hz, 1H), 6.79 (d, J = 15.7 Hz, 1H), 6.12 (d, J =
11.3 Hz, 1H), 4.96 (dd, J = 6.4, 2.7 Hz, 1H), 4.81 (d, J = 2.7 Hz, 1H), 3.65 (s, 3H), 3.51 (s, 3H), 2.24 (s,
13
3H); C NMR (101 MHz, CDCl3, TMS) δ 167.38, 166.22, 165.51, 148.36, 148.36, 136.79, 136.50,

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136.17, 133.23, 132.10, 128.78, 128.66, 127.19, 127.01, 121.97, 121.40, 111.40, 104.32, 104.32, 57.62,
56.61, 56.05, 11.59; HRMS (ESI): m/z calcd for C26H27N2O6 (M+H)+, 463.1869; found, 463.1866.
3-Substituted amino-5-(4-(dimethylamino)benzylidene)-4-methylfuran-2(5H)-one (7i) Yellow solid;
Yield: 84%; mp 85.3-86.8 ºC; 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.95–7.77 (m, 2H), 7.69 (d, J =
8.9 Hz, 1H), 7.57-7.45 (m, 4H), 7.23-7.20 (m, 2H), 6.68 (dd, J = 8.7, 6.0 Hz, 1H), 6.07 (s, 1H), 4.95 (dd,
J = 6.4, 2.7 Hz, 1H), 4.82 (dd, J = 5.0, 2.7 Hz, 1H), 3.65 (s, 3H), 3.51 (s, 3H), 3.03 (s, 6H), 2.25 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 167.44, 166.68, 166.32, 150.56, 144.82, 133.40, 132.13, 131.68, 128.69,
127.26, 121.03, 119.56, 111.98, 111.56, 104.41, 57.53, 56.62, 56.07, 40.17, 29.71, 11.65; HRMS (ESI):
m/z calcd for C26H30N3O6 (M+H)+, 480.2135; found, 480.2132.
3-Substituted amino-5-(4-methoxybenzylidene)-4-methylfuran-2(5H)-one (7j) Yellow solid; Yield:
78%; mp 159.5-161.8 ºC; 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.88 (d, J = 7.5 Hz, 2H), 7.72 (d, J
= 8.6 Hz, 2H), 7.56-7.44 (m, 3H), 7.34–7.18 (m, 1H), 6.91 (d, J = 8.6 Hz, 2H), 6.07 (s, 1H), 4.98 (dd, J =
6.2, 2.3 Hz, 1H), 4.82 (d, J = 2.3 Hz, 1H), 3.84 (s, 3H), 3.63 (s, 3H), 3.50 (s, 3H), 2.25 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 167.48, 166.46, 166.30, 160.14, 146.38, 139.18, 133.35, 132.12, 128.68, 127.27,
125.81, 120.82, 114.33, 110.15, 104.36, 57.51, 56.51, 56.08, 55.34, 11.72; HRMS (ESI): m/z calcd for
C25H27N2O7 (M+H)+, 467.1818; found, 467.1819.
3-Substituted amino-5-(4-fluorobenzylidene)-4-methylfuran-2(5H)-one (7k) Yellow solid; Yield:
53%; mp 77.7-78.5 ºC; 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.96–7.79 (m, 3H), 7.75 (dd, J = 8.8,
5.5 Hz, 2H), 7.57-7.45 (m, 4H), 7.24–7.13 (m, 1H), 7.08 (t, J = 8.7 Hz, 2H), 6.08 (s, 1H), 4.97 (dd, J =
13
6.5, 2.7 Hz, 1H), 4.82 (d, J = 2.7 Hz, 1H), 3.65 (s, 3H), 3.51 (s, 3H), 2.27 (s, 3H); C NMR (101 MHz,
CDCl3) δ 167.48, 166.44, 166.05, 147.60, 138.32, 133.30, 132.32, 132.24, 132.15, 128.71, 127.25, 121.59,
108.86, 104.38, 57.62, 56.60, 56.15, 11.81; HRMS (ESI): m/z calcd for C24H23FN2NaO6 (M+Na)+,
477.1438; found, 477.1439.
3-Substituted amino-5-benzylidene-4-methylfuran-2(5H)-one (7l) Yellow solid; Yield: 65%; mp
141.8-142.6 ºC; 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.97–7.80 (m, 3H), 7.76 (d, J = 7.4 Hz, 2H),
7.60–7.14 (m, 6H), 6.12 (s, 1H), 4.97 (dd, J = 6.5, 2.7 Hz, 1H), 4.82 (d, J = 2.8 Hz, 1H), 3.65 (s, 3H),
3.51 (s, 3H), 2.28 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.79, 167.42, 166.27, 147.95, 138.35, 133.33,
132.96, 132.14, 131.84, 130.44, 128.80, 128.71, 128.57, 127.25, 121.65, 110.12, 104.38, 103.88, 57.62,
56.60, 56.15, 11.84; HRMS (ESI): m/z calcd for C24H25N2O6 (M+H)+, 437.1713; found, 437.1711.
3-Substituted amino-5-(4-isopropylbenzylidene)-4-methylfuran-2(5H)-one (7m) Yellow solid; Yield:
1
61%; mp 95.3-94.5 ºC; H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.95–7.79 (m, 2H), 7.69 (d, J = 8.3
Hz, 2H), 7.63–7.41 (m, 4H), 7.31–7.18 (m, 2H), 6.11 (s, 1H), 4.98 (dd, J = 6.5, 2.8 Hz, 1H), 4.82 (d, J =
13
2.8 Hz, 1H), 3.64 (s, 3H), 3.50 (s, 3H), 2.92 (m, 1H), 2.27 (s, 3H), 1.26 (d, J = 6.9 Hz, 6H); C NMR
(101 MHz, CDCl3) δ 150.04, 147.37, 138.72, 133.36, 132.11, 130.57, 128.69, 128.56, 127.25, 126.94,

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121.32, 110.29, 104.36, 103.87, 57.54, 56.53, 56.12, 34.03, 23.77, 11.79; HRMS (ESI): m/z calcd for
C27H30N2NaO6 (M+Na)+, 501.2002; found, 501.2007.
3-Substituted amino-5-(2-hydroxybenzylidene)-4-methylfuran-2(5H)-one (7n) Yellow solid; Yield:
78%; mp 110.4-111.5 ºC; 1H NMR (400 MHz, acetone-d6) δ 8.98 (s, 1H), 8.03 (dd, J = 7.8, 1.4 Hz, 1H),
8.00–7.90 (m, 2H), 7.76 (d, J = 7.9 Hz, 1H), 7.62–7.44 (m, 3H), 7.27–7.10 (m, 1H), 6.96-6.92 (m, 2H),
13
6.70 (s, 1H), 5.15–4.99 (m, 1H), 4.85 (d, J = 5.1 Hz, 1H), 3.50 (s, 3H), 3.49 (s, 3H), 2.22 (s, 3H); C
NMR (101 MHz, acetone-d6) δ 168.40, 167.74, 166.56, 156.70, 148.46, 135.23, 132.66, 131.96, 131.15,
129.47, 128.49, 123.09, 121.58, 121.14, 116.54, 104.85, 104.21, 56.82, 56.63, 55.13, 11.63; HRMS
(ESI): m/z calcd for C24H24N2NaO7 (M+Na)+, 475.1481; found, 475.1483.
3-Substituted amino-4-methyl-5-(4-morpholinobenzylidene)furan-2(5H)-one (7o) Yellow solid;
1
Yield: 72%; mp 164.8-166.2 ºC; H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.88 (d, J = 7.4 Hz, 2H),
7.70 (d, J = 8.8 Hz, 2H), 7.63–7.39 (m, 3H), 7.22 (d, J = 6.2 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.06 (s,
1H), 4.97 (dd, J = 6.4, 2.6 Hz, 1H), 4.82 (d, J = 2.6 Hz, 1H), 3.96 – 3.78 (m, 4H), 3.64 (s, 3H), 3.51 (s,
13
3H), 3.35–3.18 (m, 4H), 2.25 (s, 3H); C NMR (101 MHz, CDCl3) δ 167.45, 166.40, 151.18, 145.93,
139.36, 133.37, 132.10, 131.94, 128.69, 127.26, 124.18, 120.38, 114.74, 110.56, 104.38, 66.70, 48.09,
11.71; HRMS (ESI): m/z calcd for C28H32N3O7 (M+H)+, 522.2240; found, 522.2243.
3-Substituted amino-5-((1-benzyl-1H-indol-3-yl)methylene)-4-methylfuran-2(5H)-one (7p) Yellow
solid; Yield: 74%; mp 154.3-155.7 ºC; 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.03 (s, 1H), 7.89 (d, J
= 7.2 Hz, 2H), 7.79 (dd, J = 6.4, 2.6 Hz, 1H), 7.57-7.53 (m, 1H), 7.49-7.46 (m, 2H), 7.39–7.19 (m, 8H),
7.14 (d, J = 6.8 Hz, 2H), 6.52 (s, 1H), 5.39 (s, 2H), 4.96 (dd, J = 6.4, 2.6 Hz, 1H), 4.83 (d, J = 2.6 Hz, 1H),
13
3.65 (s, 3H), 3.52 (s, 3H), 2.32 (s, 3H); C NMR (101 MHz, CDCl3) δ 167.44, 166.31, 145.17, 139.32,
136.55, 136.17, 133.41, 132.27, 132.09, 128.90, 128.69, 127.89, 127.61, 127.26, 126.69, 122.88, 120.94,
119.72, 118.46, 110.46, 109.33, 104.44, 102.77, 57.56, 56.64, 56.09, 50.74, 11.62; HRMS (ESI): m/z
calcd for C33H31N3NaO6 (M+Na)+, 588.2111; found, 588.2110.
3-Substituted amino-5-((1-(4-chlorobenzyl)-1H-indol-3-yl)methylene)-4-methylfuran-2(5H)-one (7q)
1
Yellow solid; Yield: 72%; mp 185.7-186.5 ºC; H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 8.00 (d, J =
4.2 Hz, 1H), 7.88 (s, 2H), 7.80-7.76 (m, 1H), 7.67–7.38 (m, 3H), 7.24 (dd, J = 12.6, 4.4 Hz, 6H),
7.08-7.06 (m, 2H), 6.50 (s, 1H), 5.35 (s, 2H), 4.96 (s, 1H), 4.83 (s, 1H), 3.65 (s, 3H), 3.51 (s, 3H), 2.32 (s,
13
3H); C NMR (101 MHz, CDCl3) δ 167.46, 166.35, 166.28, 145.36, 139.60, 136.00, 135.08, 132.11,
129.10, 128.70, 128.02, 127.27, 123.02, 121.08, 120.33, 118.57, 110.31, 104.45, 102.55, 99.99, 57.56,
56.62, 56.10, 50.10, 11.62; HRMS (ESI): m/z calcd for C33H30ClN3NaO6 (M+Na)+, 622.1721; found,
622.1723.
3-Substituted amino-5-((1-(4-fluorobenzyl)-1H-indol-3-yl)methylene)-4-methylfuran-2(5H)-one (7r)
Yellow solid; Yield: 68%; mp 201.2-202.7 ºC; 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.03 (s, 1H),

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7.92-7.89 (m, 2H), 7.82 (dd, J = 6.2, 2.4 Hz, 1H), 7.67-7.56 (m, 1H), 7.39–7.22 (m, 2H), 7.22–7.09 (m,
7H), 7.06-6.99 (m, 2H), 6.54 (s, 1H), 5.38 (s, 2H), 4.98 (dd, J = 7.3, 2.7 Hz, 1H), 4.86 (d, J = 2.7 Hz, 1H),
13
3.68 (s, 3H), 3.54 (s, 3H), 2.35 (s, 3H); C NMR (101 MHz, CDCl3) δ 167.45, 166.34, 166.28, 145.29,
139.31, 136.00, 133.40, 132.33, 132.10, 132.01, 128.70, 128.43, 128.35, 127.64, 127.26, 122.97, 121.03,
119.82, 118.54, 115.96, 115.74, 110.33, 109.48, 104.44, 102.61, 57.57, 56.63, 56.09, 50.05, 11.63;
HRMS (ESI): m/z calcd for C33H30FN3NaO6 (M+Na)+, 606.2016; found, 606.2014.
3-Substituted amino-4-methyl-5-((1-(3,4,5-trimethoxybenzyl)-1H-indol-3-yl) methyl-ene) furan-
2(5H)-one (7s) Yellow solid; Yield: 80%; mp 198.5-199.9 ºC; 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H),
8.03 (s, 1H), 7.96–7.83 (m, 3H), 7.86–7.76 (m, 1H), 7.68–7.41 (m, 4H), 7.40–7.14 (m, 5H), 6.53 (s, 1H),
6.38 (s, 2H), 4.97 (dd, J = 6.3, 2.7 Hz, 1H), 4.84 (d, J = 2.7 Hz, 1H), 3.82 (s, 3H), 3.76 (s, 6H), 3.66 (s,
13
3H), 3.52 (s, 3H), 2.33 (s, 3H); C NMR (101 MHz, CDCl3) δ 167.46, 166.36, 166.31, 153.64, 145.21,
139.45, 136.25, 132.15, 128.70, 127.60, 127.24, 122.92, 120.95, 119.79, 119.50, 118.50, 110.43, 110.12,
109.38, 108.01, 104.45, 104.08, 103.90, 102.77, 60.85, 57.57, 56.63, 56.17, 56.14, 56.09, 50.96, 11.61;
HRMS (ESI): m/z calcd for C36H37N3NaO9 (M+Na)+, 678.2427; found, 678.2430.
3-Substituted amino-5-((1-(benzo[d][1,3]dioxol-5-ylmethyl)-1H-indol-3-yl)methylene)-4-methyl-
furan-2(5H)-one (7t) Yellow solid; Yield: 82%; mp 123.8-124.5 ºC; 1H NMR (400 MHz, CDCl3) δ 8.28
(s, 1H), 7.99 (s, 1H), 7.88 (t, J = 6.8 Hz, 2H), 7.82-7.74 (m, 1H), 7.61–7.15 (m, 7H), 6.74 (d, J = 7.9 Hz,
1H), 6.67 (d, J = 8.0 Hz, 1H), 6.60 (d, J = 1.4 Hz, 1H), 6.51 (s, 1H), 5.91 (s, 2H), 5.27 (s, 2H), 4.96 (dd, J
= 6.4, 2.7 Hz, 1H), 4.83 (d, J = 2.7 Hz, 1H), 3.65 (s, 3H), 3.52 (s, 3H), 2.32 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 167.48, 166.36, 148.23, 147.37, 145.18, 139.42, 136.10, 133.44, 132.12, 130.38, 128.72, 127.68,
127.29, 122.91, 120.99, 120.28, 119.75, 118.51, 110.47, 109.36, 108.50, 107.34, 104.47, 102.80, 101.22,
57.57, 56.64, 56.11, 50.61, 50.61, 29.73, 11.64; HRMS (ESI): m/z calcd for C34H31N3NaO8 (M+Na)+,
632.2009; found, 632.2006.
ACKNOWLEDGEMENTS
This work was supported by the National Natural Sciences Foundations of China (No. 8112937,
U1204206), China Postdoctoral Science Foundation (No. 20100480857, 201104402) and New Teachers’
Fund for Doctor Stations, Ministry of Education (No. 20114101120013).
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