Reaction of 5-alkoxy-3,4-dihalo-2(5H)-furanones with secondary amines: Expected versus unanticipated products and their preliminary bioactivity investigations

Article abstract of DOI:10.1007/s00706-011-0594-3

Using KF as base and THF as solvent, 5-alkoxy-3,4-dihalo-2(5H)-furanones were reacted with secondary amines. The normal products, β-amino-2(5H)- furanones, were obtained via the tandem Michael addition-elimination reaction as expected in most cases. Howev

Full text of DOI:10.1007/s00706-011-0594-3

Monatsh Chem (2012) 143:443–453
DOI 10.1007/s00706-011-0594-3
ORIGINAL PAPER
Reaction of 5-alkoxy-3,4-dihalo-2(5H)-furanones with secondary
amines: expected versus unanticipated products and their
preliminary bioactivity investigations
•
Yang-Qing Mo Zhao-Yang Wang
•
•
Wen-Jie Mei Jian-Hua Fu
•
•
Yue-He Tan Shi-He Luo
Received: 25 January 2011 / Accepted: 16 July 2011 / Published online: 16 August 2011
Ó Springer-Verlag 2011
Abstract Using KF as base and THF as solvent, 5-alkoxy-
3,4-dihalo-2(5H)-furanones were reacted with secondary
amines. The normal products, b-amino-2(5H)-furanones,
were obtained via the tandem Michael addition-elimination
reaction as expected in most cases. However, the reaction
between diisopropylamine and 3,4-dihalo-5-methoxy-
2(5H)-furanones yielded unanticipated products, methyl
(E)-2-halo-4-(diisopropylamino)-4-oxobut-2-enoates. The
possible synthetic mechanism involving a rearrangement
reaction was proposed. The biological activity assay of
products derived from the reactions of 5-alkoxy-3,4-dihalo-
2(5H)-furanones with different amino compounds was
preliminarily investigated by the MTT method on A549
cells in vitro, which revealed that some derivatives of amino
acid esters with a benzene ring exhibited the best anticancer
bioactivity.
Introduction
Molecules possessing a 2(5H)-furanone moiety, a kind of
a,b-unsaturated lactone substructure frequently found in
natural products, have received considerable interest
because of their significant biological activities, such as
antifungal, antibacterial, anti-inflammatory, and antitumor
[1–4]. Therefore, the synthesis of different 2(5H)-fura-
nones and their applications in the preparation have drawn
much attention [5–16].
Tandem reactions have been extensively applied in
organic synthesis because of their higher yield and sim-
pler operation without isolation of intermediates than
traditional methods [17–19]. For example, recently more
and more attention has been attracted by applications of
the tandem Michael addition-elimination reaction in the
synthesis of bioactive compounds and natural products
[20–24].
Keywords b-Amino-2(5H)-furanone ꢀ Antitumor agents ꢀ
Tandem Michael addition-elimination reaction ꢀ
X-Ray structure determination ꢀ Reaction mechanisms ꢀ
Rearrangements
For a long time, the tandem Michael addition-elimination
reaction of 3,4-dihalo-2(5H)-furanones with nucleophiles
containing different heteroatoms, including nitrogen
[25–32], sulfur [33–36], phosphorus [37, 38], and selenium
[39], has been one of the research focuses in furanone
chemistry. Based on previous work on the tandem reaction of
5-alkoxy-3,4-dihalo-2(5H)-furanones 1 with primary amino
nucleophiles, such as a,x-diamines [30], a-amino acid
esters [31], and a-amino acids [32], we further investigated
the reaction of 1 with secondary amines (Scheme 1). The
structural characterization showed that the products were, in
most cases, the expected b-amino-2(5H)-furanones 2a–2j
and similar to those reported before [29–32]. Surprisingly,
the reaction between diisopropylamine, a secondary amine
with more steric hindrance, and 3,4-dihalo-5-methoxy-
2(5H)-furanones 1a, 1b gave some unanticipated ring-
opening products, 3a, 3b.
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-011-0594-3) contains supplementary
material, which is available to authorized users.
Y.-Q. Mo ꢀ Z.-Y. Wang (&) ꢀ J.-H. Fu ꢀ Y.-H. Tan ꢀ S.-H. Luo
Department of Chemistry, School of Chemistry and
Environment, South China Normal University,
Guangzhou 510006, People’s Republic of China
e-mail: wangwangzhaoyang@tom.com; wangzy@scnu.edu.cn
W.-J. Mei
School of Pharmacy, Guangdong Pharmaceutical University,
Guangzhou, Guangdong 510006, People’s Republic of China
123

444
Y.-Q. Mo et al.
Scheme 1
R2N
X
4
3
R2NH
2a: X=Br, R=CH2CH3
2b: X=Cl, R=CH2CH3
2c
2
X
X
5
6
(R=Et, Pr)
: X=Br, R=CH2CH2CH3
2d
H3CO
O
X
1
O
-
: X=Cl, R=CH2CH2CH3
KF
2a 2d
O
H3CO
O
THF
r.t.
H
3
2
1a, 1b
1b
R2NH
N
1a
: X=Br; : X=Cl
4
1
OCH3
(R= i-Pr)
O
O
3a, 3b
3a: X=Br; 3b: X=Cl
14
15
R2N
X
R2NH
X
X
13
7
10 11
4
3
M*O
6
(R=Et, Pr, i-Pr)
O
H
5
2
*
8
9
O
O
H
S
*
KF, THF, r.t.
O
12
(M*)
O1
S
2e-2j
1c, 1d
2e
2h
: X=Cl, R=CH2CH2CH3
2i: X=Br, R=CH(CH3)2
: X=Br, R=CH2CH3
2f: X=Cl, R=CH2CH3
2g: X=Br, R=CH2CH2CH3 2j: X=Cl, R=CH(CH3)2
1c
: X=Br; : X=Cl
1d
Results and discussion
took place easily, and it is an exothermic reaction. For the
same reason, all reactions were carried out at room
temperature.
Effects of reaction conditions on the syntheses of new
compounds
Besides, different secondary amines also affected the
yield. Generally, more sterically hindered reagents resulted
in a lower yield of the products. Therefore, the reaction of
diethylamine gave the highest yield, whereas the yield for
diisopropylamine was the lowest. However, for the sub-
strates, the effect of steric hindrance in the 5-alkoxy-3,4-
dihalo-2(5H)-furanones on the yield was small.
Taking the reaction of 3,4-dichloro-5-methoxy-2(5H)-
furanone (1b) with diethylamine as an example, the effects
of different bases and reaction time on the yield of 2b were
discussed (Table 1).
The results showed that the bases had different effects
on the reaction yield, and the best base was KF for the
highest yield in the shortest time according to TLC moni-
toring (Table 1, entry 2). Once the reaction time was
increased to 4 h, the yield dropped (entry 4), which indi-
cated that 2 h was suitable for this reaction (entry 2).
At the same time, the exploration experiments also
showed that it was necessary to drip the liquid secondary
amine into the reaction system in half an hour to make the
operation safer and to get the higher yield. This may be
because the tandem Michael addition-elimination reaction
Structure characterization of the new compounds
The structure of the new compounds was systematically
1
characterized by specific rotation, UV-Vis, IR, H NMR,
13C NMR, MS, elemental analysis, and X-ray single crystal
diffraction. The results showed that the unanticipated
products 3a and 3b were obtained.
In the IR spectra, the absorption band of the unsaturated
C–H bond at 3,016 cm-1 was observed for 3a and 3b (the
IR spectrum of compound 3b as a representative is shown as
Fig. 1a), whereas for other normal products only an
absorption band appeared at 2,860–2,980 cm-1, indicating
the saturated C–H bond (the IR spectrum of compound 2h
as a representative is shown as Fig. 1b). However, other
Table 1 The exploration of reaction conditions for 2b
Entrya
Base
t/h
Yield/%
1
2
3
4
a
Et3N
KF
48b
2b
8b
4
27
63
45
59
1
conventional characterization methods including H NMR
and 13C NMR could not give strong evidence for 3a and 3b.
Only the results of X-ray single crystal diffraction for
the compounds 3b (Fig. 2) and 2h (Fig. 3) gave convincing
evidence. The molecular structure of compound 3b is
shown in Fig. 2, which obviously reveals that there is no
furanone ring in 3b.
DABCO
KF
Reaction conditions: 1 mmol 3,4-dichloro-5-methoxy-2(5H)-fura-
none (1b), 3 cm3 diethylamine, 3 cm3 THF, base dosage 4 equiv.;
room temperature
b
According to TLC monitoring, the time is that when the substrate
1b disappeared completely
The molecular structure of compound 2h is shown in
Fig. 3, which reveals that it contains one five-membered
DABCO 1,4-Diazabicyclo[2.2.2]octane
123

Reaction of 5-alkoxy-3,4-dihalo-2(5H)-furanones with secondary amines
445
atom connected to the double bond made them more active,
but these molecules with multi-functional groups were
usually synthesized via multiple steps [40–44]. The unex-
pected results may provide a simple method to synthesize
them. Therefore, it is necessary to understand the formation
mechanism of unanticipated compounds under this exper-
imental condition.
Suppose that the reaction of 3,4-dichloro-5-methoxy-
2(5H)-furanone (1b) and diisopropylamine gave compound
3b0 (isomer of 3b, Scheme 2), an expected product without
ring-opening according to the normal mechanism of the
tandem Michael addition-elimination reaction [25–32]. In
order to study the stability, the geometry optimizations and
frequency calculations of 3b and 3b0 were implemented in
Gaussian 03 [45]. Density functional methods (DFT) using
the gradient-corrected Becke’s three-parameter exchange
functional (B3) and Lee-Yang-Parr (LYP) correlation
functional with Pople’s 6-31G basis set were used. To get
more reasonable results, the geometry optimizations of the
different tautomers were further performed using the sec-
´
ond-order Møller-Plesset perturbation theory (MP2) with
the 6-311G(d,p) basis set [46–48]. The results showed that
the total energies of 3b and 3b0 were -3065.978 9
103 kJ mol-1 and -3066.376 9 103 kJ mol-1, respec-
tively, indicating that 3b is energetically less stable than
3b0.
Combining the theoretical calculations with experi-
mental phenomena that the exothermic reaction easily took
place in several hours, we assumed that the unanticipated
compound 3b could be formed according to the mechanism
outlined in Scheme 2. Once the normal product 3b0 was
formed via the tandem Michael addition-elimination reac-
tion [25–32], both the reaction heat and the higher steric
hindrance caused by the diisopropylamino group may
promote the rearrangement of 3b0.
Fig. 1 The infrared spectra of compounds 3b (a) and 2h (b)
furanone ring together with one six-membered cyclohex-
ane ring. The five atoms O(2)–C(1)–C(2)–C(3)–C(10) in
the furanone ring are in the same plane. The cyclohexane
ring exhibits a chair-like configuration, and the bonds of
three substituent groups linked to the ring are equatorial.
Besides, the molecule 2h possesses four chiral centers:
C10(S), C11(R), C13(R), and C17(S). It should be
emphasized that C(10) takes an S configuration, indicating
the chiral intermediate 1d can keep its configuration
unchanged during the reaction.
Firstly, the methoxy was removed via hydrolysis by a
small amount of water in the reaction system (in fact, even
if the dosage of water is only the catalytic amount, it is also
enough). Then, ring opening and the following esterifica-
tion gave the intermediate A. Of course, direct 1,4-methoxy
migration1 [49–52] of 3b0 and cleavage of the C–O bond
(which is highlighted by red lines in Scheme 2) also may
lead to the formation of intermediate A. The elimination of
diisopropylamine from intermediate A could give the
propadienone2 [48, 53–60] intermediate B. Finally, the
quick addition of diisopropylamine with propadienone
B and following isomerization of the enol reasonably
produced the abnormal compound 3b.
Plausible rearrangement reaction mechanism
for the formation of the unanticipated products
The results of FTIR and especially X-ray single crystal
diffraction showed that compounds 3a and 3b were not
ring compounds. Generally, these unsaturated conjugate
compounds containing both ester and amide structure are
important organic intermediates. In particular, the halogen
1
Some literature on alkoxy migration (especially involving in the
1,4-methoxy migration and the migration on five-membered rings).
2
Some literature involving the formation of different propadienones.
123

446
Y.-Q. Mo et al.
Fig. 2 The molecular structure
of compound 3b
Fig. 3 The molecular structure
of compound 2h
During the rearrangement, three indispensable factors,
including the exothermic reaction heat, the higher steric
hindrance caused by the diisopropylamino group, and the
migration ability of alkoxy (or the reactivity of the corre-
sponding alkyl alcohol), are important. For other second
amines, the steric hindrance caused by the amino group in
the product of the tandem reaction is lower than that caused
by the diisopropylamino group; for menthyloxy, the
migration ability (or the reactivity of menthol) is lower
than that of methoxy. Therefore, only 4-(diisopropyl-
amino)-3-halo-5-methoxy-2(5H)-furanones 3b0 (3a0) were
rearranged to 3b (3a).
Perhaps the normal intermediates 3a0, 3b0 in Scheme 2
were not yielded at all, and 3a, 3b were formed via another
rearrangement mechanism (Scheme 3). Here, we may
assume that the steric hindrance of diisopropylamine can
123

Reaction of 5-alkoxy-3,4-dihalo-2(5H)-furanones with secondary amines
447
Scheme 2
N
Cl
N
Cl
N
Cl
Hydrolysis
Ring opening
H2O
O
HO
O
H
C
H3CO
O
O
O
3b'
CH3OH
O
HO
1,4-methoxy migration
Cl
HN
N
Cl
O
C
Esterification
OCH3
OCH3
H
OCH3
Cl
Elinmination
CH3OH
H2O
O
B
O
O
A
H
Cl
HN
C
C
OCH3
O
HO
Isomerization
C
O
N
O
N
Addition
3b
Scheme 3
Cl
Cl
Cl
Cl
O
Cl
Cl
HN
OH
H3CO
O
O
H3CO
H3CO
O
O
1,2-Addition
NHR2
NR2
1b
(R = isopropyl)
H
Ring opening
Cl
Cl
Cl
H
Cl
Cl
Cl
1,2-
hydrogen
shift
H
OH
OH
OH
NR2
H3CO
H3CO
O
H3CO
O
O
NR2
NR2
Tautomerization
Cl
H
Cl
Cl
Cl
OCH3
O
H
Elimination
O
O
H3CO
H3CO
N
O
O
O
HCl
NR2
NR2
3b
Inhibition activity of compounds 2–7 on A549 cells
in vitro
inhibit the desired tandem Michael addition-elimination
reaction. And the amine could attack the C-2 carbon atom
of the furanone system, which causes the opening of the
ring at C-2. The key step of the rearrangement would be the
1,2-hydrogen shift from the hemiacetal carbon C-4 atom
(former C-5 of the furanone ring) to the C-3 atom, which
has a positive charge because of the resonance of an allylic
carbocation formed during the opening of the furanone
ring. Further elimination of HCl and tautomerization leads
directly to the isolated products 3a, 3b.
As an important component of the living organisms, amino
acids play a crucial role in different vital phenomena. It is
reported that the need of tumor cells for amino acids is
different from the normal cells, and the introduction of
amino acids into anti-tumor drugs could improve the
selectivity to tumor cells and the lipophilicity of the drugs
[61–63]. Moreover, some b-amino-2(5H)-furanones also
123

448
Y.-Q. Mo et al.
Fig. 4 b-Amino-2(5H)-
furanones synthesized
previously [29–32]
CH3
N
CH3
CH3
CH3
Cl
N
Br
H
H3CO
4a
O
O
O
[29]
MO*
O
[29]
4b
H
H3CO
HN
M*O
HN
O
O
5g: X= Cl, n=1
5h
: X= Br, n=1
5a:
X= Cl, n=1
O
O
5i: X= Cl, n=2
5j: X= Br, n=2
5k: X= Cl, n=3
5l: X= Br, n=3
5m:X= Cl, n=5
5n: X= Br, n=5
n
n
5b
: X= Br, n=1
X
X
HN
H3CO
X
HN
X
5c: X= Cl, n=2
5d: X= Br, n=2
H
5e
: X= Cl, n=3
O
O
5f
: X= Br, n=3
O
O
M*O
5a 5f
-
[30]
5g-5n [30]
R
R
6a: X=Br, R=H, R'=CH3
6b: X=Cl, R=H, R'=CH3
H
COOR'
HN
H
COOH
O
X
6c: X=Cl, R=CH2CH(CH3)2,R'=CH3
HN
X
6d
: X=Br, R=CH3, R'=CH3
H
6e
: X=Cl, R=CH3, R'=CH3
H3CO
O
O
6f: X=Cl, R=CH2Ph, R'=CH2CH3
M*O
O
6a-6f [31]
7a-7j [32]
7a
: X=Cl, R=CH3
6g: X=Br, R=H, R'=CH3
7b
: X=Br, R=CH3
R
H
6h
: X=Cl, R=H, R'=CH3
7c: X=Cl, R=CH2Ph
7d: X=Br, R=CH2Ph
6i
: X=Br, R=CH2CH(CH3)2,R'=CH3
6j: X=Cl, R=CH2CH(CH3)2,R'=CH3
6k: X=Br, R=CH3, R'=CH3
COOR'
7e
: X=Cl, R=CH2CH(CH3)2
HN
X
7f
: X=Br, R=CH2CH(CH3)2
6l: X=Cl, R=CH3, R'=CH3
7g: X=Cl, R=CH(CH3)2
7h: X=Br, R=CH(CH3)2
7i: X=Cl, R=H
H
6m
:X=Br, R=CH2Ph, R'=CH2CH3
6n: X=Cl, R=CH2Ph, R'=CH2CH3
M*O
O
O
6o: X=Br, R=CH(CH3)CH2CH3, R'=CH3
6p: X=Cl, R=CH(CH3)CH2CH3, R'=CH3
7j
: X=Br, R=H
6g-6p [31]
show certain biological activity [28]. Thus, in order to find
2(5H)-furanones with better physiological activity, we also
preliminarily tested the biological activities of the products
2–7 derived from different 5-alkoxy-3,4-dihalo-2(5H)-
furanones and nucleophiles containing nitrogen (com-
pounds 4–7 synthesized before [29–32], Fig. 4).
exhibited relatively lower inhibition (Table 2, entries
15–28), indicating that more furanone rings contained in
the compounds do not improve the bioactivity. If com-
pounds 2–4 are regarded as the products derived from
secondary amines (HNR2), there was little effect on the
bioactivity whether the R group was methyl, ethyl, propyl,
or isopropyl (entries 1–14). Only the product 2b showed
the best inhibition, but it was just 80.5% (entry 2).
The bioactivity of the obtained b-amino-2(5H)-fura-
nones 2–7 on A549 cells in vitro was investigated by the
MTT method [64] (Table 2), and the results showed that
some products had anticancer biological activity.
Interestingly, the inhibition activity of compounds 7, the
products directly synthesized from the unprotected amino
acids [32] (Table 2, entries 45–54), was not as good as
compounds 6, the products derived from amino acid esters
[31] (entries 29–44). Among 7, the inhibition of 7f was best
(entry 50), but it was worse than that of many products
derived from secondary amines. Therefore, the products
containing a free amino acid unit unexpectedly showed
worse inhibition, which may be related to the lower lipo-
philicity of the potential drug.
In most cases, the inhibition increased with sample
concentration, which was similar to the results reported
before [64]. Under the same sample concentration, men-
thyloxy and methoxy as 5-substituents in b-amino-2(5H)-
furanones have no obvious influence on the inhibition. In
other words, the bioactivity of b-amino-2(5H)-furanones
seems to be independent on the 5-substituent and its ste-
reochemistry. Similarly, the halogen at 4-position also
seems to have nothing to do with the bioactivity.
By contrast, b-amino-2(5H)-furanones containing amino
acid esters exhibited the best bioactivity because of both
the introduction of amino acids into anti-tumor drugs
From the compounds possessing different amino groups,
compounds 5, the products derived from diamines [30],
123

Reaction of 5-alkoxy-3,4-dihalo-2(5H)-furanones with secondary amines
449
Table 2 Inhibition activity of compounds 2–7 on A549 cells in vitro
at different concentrations
Table 2 continued
Entry
Compound
Inhibition at different concentration/%
Entry
Compound
Inhibition at different concentration/%
50 lM
100 lM
50 lM
100 lM
47
48
49
50
51
52
53
54
7c
7d
7e
7f
-3.20
9.90
3.10
17.40
13.00
41.00
22.20
17.10
3.10
1
2a
2b
2c
2d
2e
2f
10.50
69.60
9.00
69.40
80.50
28.40
-1.20
10.30
46.50
78.40
6.40
2
-0.10
9.30
3
4
4.00
7g
7h
7i
5.30
5
12.10
51.10
70.90
-2.80
7.30
8.10
6
4.90
7
2g
2h
2i
7j
2.50
1.90
8
9
8.10
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
2j
6.40
10.20
77.20
48.70
3.90
[61–63] and still keeping their better lipophilicity by the
ester group. Especially the inhibitions of 6f, 6l, 6m, 6n, and
6o at the concentration of 100 lM were 89.7% (Table 2,
entry 34), 90.4, 85.4, 91.8, and 97.2%, respectively (entries
40–43). In view of the structure of 6f, 6m, and 6n, the
existence of a benzene ring improved the bioactivity. But
for compounds 7c and 7d, the inhibition was not increased
significantly (entries 47 and 48), which further demon-
strated that keeping better lipophilicity by the ester group
was important.
3a
3b
4a
4b
5a
5b
5c
5d
5e
5f
47.40
29.20
4.60
5.90
6.40
6.00
1.30
8.00
6.80
13.30
7.90
15.40
8.80
5.70
22.90
16.50
-0.04
4.30
8.10
In summary, the reaction of 5-alkoxy-3,4-dihalo-2(5H)-
furanones with various amino compounds was investi-
gated. In most cases, the expected b-amino-2(5H)-furanone
derivatives were successfully synthesized via the tandem
Michael addition-elimination. However, the reaction
between diisopropylamine and 3,4-dihalo-5-methoxy-
2(5H)-furanones surprisingly gave unanticipated products
without a furanone ring via a possible rearrangement
mechanism. The biological activities of the obtained series
compounds on A549 cells in vitro were investigated by the
MTT assay. The products derived from amino acid esters,
especially those containing a benzene ring, showed
remarkable anticancer activity. These new results are
beneficial to the studies of novel reactions of 2(5H)-fura-
none and the applications of 2(5H)-furanone in organic
synthesis or potential drugs.
5g
5h
5i
11.60
8.60
-0.04
7.60
-0.09
8.50
5j
5k
5l
3.10
1.10
-0.40
-22.90
5.10
-1.90
-28.00
1.40
5m
5n
6a
6b
6c
6d
6e
6f
-1.30
13.80
0.90
-1.00
18.50
2.10
-60.20
0.50
0.70
5.60
89.10
-4.60
-2.30
3.00
89.70
-7.80
5.70
6g
6h
6i
8.70
6j
-4.30
6.50
3.90
Experimental
6k
6l
6.20
All melting points were determined on an X-5 digital
melting point apparatus. Infrared spectra were recorded on
a Bruker Vector 33 FT-IR instrument as KBr pellets in the
90.20
77.40
70.20
82.70
29.80
4.30
90.40
85.40
91.80
97.20
28.50
11.70
11.60
6m
6n
6o
6p
7a
7b
1
absorption range of 4,000–400 cm-1. H and 13C NMR
spectra were obtained in CDCl3 on a Varian DRX-
400 MHz spectrometer and tetramethylsilane (TMS) was
used as an internal standard. UV absorption peaks were
measured by a Shimazu UV-2550 ultraviolet absorption
4.30
123

450
Y.-Q. Mo et al.
3-Bromo-4-(dipropylamino)-5-methoxy-2(5H)-furanone
(2c, C11H18BrNO3)
detector with dichloromethane as a solvent. Optical rota-
tions were determined with an Autopol IV polarimeter in
C2H5OH in a 10-cm cell, and mass spectra were recorded
on a Thermo LCQ DECA XP MAX mass spectrometer.
Elemental analyses were taken on a Perkin Elmer CHN
2400 elemental analyzer.
1
Yellow liquid, yield 55%; H NMR (400 MHz, CDCl3):
d = 0.85 (t, J = 7.2 Hz, 6H, 2CH3), 1.54–1.64 (m, 4H,
2CH2), 3.20–3.59 (m, 7H, 2NCH2, OCH3), 5.62 (s, 1H,
CH-5) ppm; 13C NMR (100 MHz, CDCl3): d = 10.76,
22.34, 29.61, 54.51, 85.28, 97.49, 154.73, 168.32 ppm; IR
All reagents and solvents were commercially available
and used as received. Using furfural, natural menthol, and
methanol as starting materials, 5-alkoxy-3,4-dihalo-2(5H)-
furanones 1a–1d were prepared according to the literature
[29–32].
ꢀ
(KBr): m = 2,956, 2,934, 2,874, 1,755, 1,616, 1,116, 983,
745, 691 cm-1; UV (CH2Cl2): kmax = 283 nm; ESI–MS:
m/z = 292 ([M ? H]?, 100).
3-Chloro-4-(dipropylamino)-5-methoxy-2(5H)-furanone
(2d, C11H18ClNO3)
1
Yellow liquid, yield 57%; H NMR (400 MHz, CDCl3):
General procedure for the reaction of 5-alkoxy-3,4-
dihalo-2(5H)-furanones with secondary amines
d = 0.83 (t, J = 7.2 Hz, 6H, 2CH3), 1.52–1.62 (m, 4H,
2CH2), 3.17–3.23 (m, 4H, 2NCH2), 3.39 (s, 3H, OCH3), 5.61
(s, 1H, CH-5) ppm; 13C NMR (100 MHz, CDCl3):
d = 10.74, 22.33, 29.59, 54.56, 85.13, 97.49, 154.75,
The reaction of 5-alkoxy-3,4-dihalo-2(5H)-furanones 1a–
1d (1 mmol) with excess secondary amine (3 cm3) was
carried out in 3 cm3 THF at room temperature in the
presence of KF (4 mmol) under N2 atmosphere.
According to TLC monitoring (ethyl acetate/petroleum
ether 1/15), once the reaction was complete (about 2 h),
the mixture was washed with saturated NaCl solution
and then extracted with CH2Cl2. The solvent was
removed in vacuo, and the residue was purified by col-
umn chromatography on silica gel with gradient eluent
(mixtures of petroleum ether and ethyl acetate with
different volume ratios) to give the products 2a–2j and
3a–3b for analysis.
ꢀ
168.32 ppm; IR (KBr): m = 2,966, 2,934, 2,877, 1,760,
1,626, 1,120, 984, 746 cm-1
;
UV (CH2Cl2):
kmax = 288 nm; ESI–MS: m/z = 248 ([M ? H]?, 100).
(5S)-3-Bromo-4-(diethylamino)-5-menthyloxy-2(5H)-
furanone (2e, C18H30BrNO3)
1
Yellow liquid, yield 66%; H NMR (400 MHz, CDCl3):
d = 0.76 (d, J = 6.8 Hz, 3H, CH3-12), 0.82–0.92 (m, 7H,
CH-13, CH3-14, CH3-15), 0.99–1.11 (m, 2H, CH2-9),
1.14–1.21 (m, 6H, 2CH3 of NEt2), 1.40–1.47 (m, 2H, CH-
8, CH-11), 1.67–1.71 (m, 2H, CH2-10), 1.89–2.08 (m, 2H,
CH2-7), 3.31 (q, J = 6.8 Hz, 2H, NCH2), 3.44 (q,
J = 6.8 Hz, 2H, NCH2), 4.76–4.83 (ddd, J1 = 4.0 Hz,
J2 = 4.0 Hz, J3 = 4.0 Hz, 1H, CH-6), 6.74 (s, 1H, CH-5)
ppm; 13C NMR (100 MHz, CDCl3): d = 12.71, 14.05,
16.00, 20.76, 21.91, 23.12, 25.86, 31.36, 34.06, 39.31,
40.15, 42.52, 46.88, 77.15, 128.73, 132.07, 161.08,
3-Bromo-4-(diethylamino)-5-methoxy-2(5H)-furanone
(2a, C9H14BrNO3)
Yellowish liquid, yield 61%; 1H NMR (400 MHz, CDCl3):
d = 1.11–1.20 (m, 6H, 2CH3), 3.27 (q, J = 6.8 Hz, 2H,
NCH2), 3.37 (q, J = 6.4 Hz, 2H, NCH2), 3.77 (s, 3H,
OCH3), 6.91 (s, 1H, CH-5) ppm; 13C NMR (100 MHz,
CDCl3): d = 12.55, 14.09, 39.48, 42.46, 53.38, 118.48,
ꢀ
163.36 ppm; IR (KBr): m = 2,957, 2,871, 1,729, 1,646,
1,434, 1,306, 1,222, 970, 516 cm-1; UV (CH2Cl2):
kmax = 258 nm; ESI–MS: m/z = 388 ([M ? H]?, 100);
[a]2D0 = ? 21.90° cm2 g-1 (c = 0.36, CH3CH2OH).
ꢀ
135.48, 162.73, 163.62 ppm; IR (KBr): m = 2,974, 2,879,
1,739, 1,640, 1,436, 1,224, 1,148, 958, 611 cm-1
;
UV (CH2Cl2): kmax = 260 nm; ESI–MS: m/z = 264
([M ? H]?, 100).
(5S)-3-Chloro-4-(diethylamino)-5-menthyloxy-2(5H)-
furanone (2f, C18H30ClNO3)
1
Yellow liquid, yield 63%; H NMR (400 MHz, CDCl3):
3-Chloro-4-(diethylamino)-5-methoxy-2(5H)-furanone
(2b, C9H14ClNO3)
d = 0.76 (d, J = 6.8 Hz, 3H, CH3-12), 0.82–0.92 (m, 7H,
CH-13, CH3-14, CH3-15), 1.02–1.08 (m, 2H, CH2-9), 1.17
(t, J = 7.2 Hz, 6H, 2CH3 of NEt2), 1.40–1.47 (m, 2H, CH-
8, CH-11), 1.67–1.70 (m, 2H, CH2-10), 1.92–2.10 (m, 2H,
CH2-7), 3.32 (q, J = 7.2 Hz, 2H, NCH2), 3.43 (q,
J = 6.8 Hz, 2H, NCH2), 4.74–4.81 (ddd, J1 = 4.4 Hz,
J2 = 4.0 Hz, J3 = 4.4 Hz, 1H, CH-6), 6.93 (s, 1H, CH-5)
ppm; 13C NMR (100 MHz, CDCl3): d = 12.71, 14.13,
16.00, 20.78, 21.93, 23.11, 25.84, 31.37, 34.08, 39.42,
40.10, 42.44, 46.91, 77.23, 119.10, 135.26, 161.65,
Yellowish liquid [25], yield 63%; 1H NMR (400 MHz,
CDCl3): d = 1.11–1.15 (m, 6H, 2CH3), 3.28 (q,
J = 5.2 Hz, 2H, NCH2), 3.40 (q, J = 5.2 Hz, 2H,
NCH2), 3.79 (s, 3H, OCH3), 6.74 (s, 1H, CH-5) ppm;
13C NMR (100 MHz, CDCl3): d = 12.53, 14.01, 39.34,
42.54, 53.27, 128.30, 132.31, 162.13, 163.28 ppm;
ꢀ
IR (KBr): m = 2,979, 2,934, 2,879, 1,743, 1,640,
1,436, 1,320, 1,225, 1,151, 1,043, 958, 772 cm-1
;
UV (CH2Cl2): kmax = 266 nm; ESI–MS: m/z = 220
([M ? H]?, 100).
ꢀ
163.74 ppm; IR (KBr): m = 2,957, 2,935, 2,871, 1,732,
123

Reaction of 5-alkoxy-3,4-dihalo-2(5H)-furanones with secondary amines
451
1,646, 1,457, 1,311, 1,223, 1,149, 1,016, 958, 752 cm-1
;
2,929, 2,871, 1,722, 1,645, 1,446, 1,335, 1,217, 1,136, 982,
611 cm-1
; UV (CH2Cl2): kmax = 265 nm; ESI–MS:
UV (CH2Cl2): kmax = 253 nm; ESI–MS: m/z = 366
([M ? Na]?, 100); [a]D20 = ? 31.20° cm2 g-1 (c = 0.32,
CH3CH2OH).
m/z = 416 ([M ? H]?, 100); [a]2D0 = ? 15.80° cm2 g-1
(c = 0.56, CH3CH2OH).
(5S)-3-Bromo-4-(dipropylamino)-5-menthyloxy-2(5H)-
furanone (2g, C20H34BrNO3)
(5S)-3-Chloro-4-(diisopropylamino)-5-menthyloxy-2(5H)-
furanone (2j, C20H34ClNO3)
White solid, yield 59%; m.p.: 94.2–95.0 °C; 1H NMR
(400 MHz, CDCl3): d = 0.76 (d, J = 5.6 Hz, 3H, CH3-
12), 0.82–0.97 (m, 13H, CH-13, CH3-14, CH3-15, 2CH3 of
NPr2), 1.04–1.13 (m, 2H, CH2-9), 1.22–1.37 (m, 2H, CH-8,
CH-11), 1.62–1.64 (m, 6H, CH2-10, 2CH2 of NPr2),
2.14–2.18 (m, 2H, CH2-7), 3.05–3.22 (m, 2H, NCH2),
3.51–3.57 (m, 1H, CH-6), 3.65–3.74 (m, 2H, NCH2), 5.75
(s, 1H, CH-5) ppm; 13C NMR (100 MHz, CDCl3):
d = 10.73, 15.94, 21.21, 22.17, 22.33, 22.76, 25.15,
31.65, 33.91, 42.44, 48.19, 72.36, 79.91, 97.84, 158.51,
Yellowish liquid, yield 53%; H NMR (400 MHz, CDCl3):
1
d = 0.65 (d, J = 6.8 Hz, 3H, CH3-12), 0.74–0.81 (m, 7H,
CH-13, CH3-14, CH3-15), 0.92–1.02(m, 2H, CH2-9), 1.09 (d,
J = 6.0 Hz, 6H, 2CH3 of N(i-Pr2)), 1.35 (d, J = 6.8 Hz, 6H,
2CH3 of N(i-Pr2)), 1.38–1.39 (m, 2H, CH-8, CH-11),
1.57–1.60 (m, 2H, CH2-10), 1.78–1.95 (m, 2H, CH2-7),
3.36–3.44 (m, 1H, NCH), 3.78–3.85 (m, 1H, NCH),
4.67–4.75 (ddd, J1 = 4.0 Hz, J2 = 4.4 Hz, J3 = 4.4 Hz,
1H, CH-6), 6.62 (s, 1H, CH-5) ppm; 13C NMR (100 MHz,
CDCl3): d = 15.96, 20.07, 20.20, 20.60, 20.64, 20.69, 21.90,
23.04, 25.80, 31.31, 34.02, 40.12, 45.64, 46.74, 50.39, 76.88,
ꢀ
168.99 ppm; IR (KBr): m = 2,961, 2,868, 1,746, 1,618,
1,457, 1,315, 1,244, 963, 530 cm-1; UV (CH2Cl2):
kmax = 289 nm; ESI–MS: m/z = 416 ([M ? H]?, 100);
[a]2D0 = ? 31.30° cm2 g-1 (c = 0.25, CH3CH2OH).
126.82, 134.59, 160.91, 162.87 ppm; IR (KBr): m = 2,959,
ꢀ
2,930, 2,872, 1,725, 1,643, 1,446, 1,342, 1,224, 1,136, 1,017,
962, 745 cm-1; UV (CH2Cl2): kmax = 261 nm; ESI–MS:
m/z = 394 ([M ? Na]?, 100); [a]2D0 = -23.40° cm2 g-1
(c = 0.16, CH3CH2OH).
(5S)-3-Chloro-4-(dipropylamino)-5-menthyloxy-2(5H)-
furanone (2h, C20H34ClNO3)
1
White solid, yield 58%; m.p.: 100.5–101.2 °C; H NMR
(E)-Methyl 2-bromo-4-(diisopropylamino)-4-oxobut-2-
enoate (3a, C11H18BrNO3)
(400 MHz, CDCl3): d = 0.76 (d, J = 6.0 Hz, 3H, CH3-
12), 0.82–0.97 (m, 13H, CH-13, CH3-14, CH3-15, 2CH3 of
NPr2), 1.04–1.13 (m, 2H, CH2-9), 1.22–1.37 (m, 2H, CH-8,
CH-11), 1.61–1.68 (m, 6H, CH2-10, 2CH2 of NPr2),
2.11–2.18 (m, 2H, CH2-7), 3.05–3.23 (m, 2H, NCH2),
3.51–3.57 (ddd, J1 = 2.0 Hz, J2 = 2.0 Hz, J3 = 2.0 Hz,
1H, CH-6), 3.65–3.77 (m, 2H, NCH2), 5.75 (s, 1H, CH-5)
ppm; 13C NMR (100 MHz, CDCl3): d = 10.82, 15.93,
21.22, 22.17, 22.41, 22.76, 25.16, 31.67, 33.90, 42.44,
48.20, 51.98, 80.01, 96.93, 156.03, 168.57 ppm; IR (KBr):
1
White needles, yield 51%; m.p.: 54.8–56.1 °C; H NMR
(400 MHz, CDCl3): d = 1.10 (d, J = 6.4 Hz, 6H, 2CH3 of
N(i-Pr2)), 1.35 (d, J = 6.8 Hz, 6H, 2CH3 of N(i-Pr2)),
3.39–3.44 (m, 1H, NCH), 3.72 (s, 3H, OCH3), 3.79–3.87
(m, 1H, NCH), 6.94 (s, 1H, CH-3) ppm; 13C NMR
(100 MHz, CDCl3): d = 19.99, 20.61, 45.72, 50.41, 53.26,
ꢀ
115.76, 139.34, 162.12, 163.47 ppm; IR (KBr): m = 3,016,
2,978, 2,871, 1,738, 1,638, 1,618, 1,440, 1,221, 1,031,
968, 608 cm-1; UV (CH2Cl2): kmax = 265 nm; ESI–MS:
m/z = 292 ([M ? H]?, 100).
ꢀ
m = 2,963, 2,918, 2,874, 1,748, 1,624, 1,336, 1,248, 968,
749 cm-1
; UV (CH2Cl2): kmax = 286 nm; ESI–MS:
(E)-Methyl 2-chloro-4-(diisopropylamino)-4-oxobut-2-
enoate (3b, C11H18ClNO3)
m/z = 372 ([M ? H]?, 100); [a]2D0 = -23.50° cm2 g-1
(c = 0.56, CH3CH2OH).
1
White needles, yield 53%; m.p.: 77.6–79.0 °C; H NMR
(5S)-3-Bromo-4-(diisopropylamino)-5-menthyloxy-2(5H)-
furanone (2i, C20H34BrNO3)
(400 MHz, CDCl3): d = 1.06 (d, J = 6.8 Hz, 6H, 2CH3 of
N(i-Pr2)), 1.32 (d, J = 6.8 Hz, 6H, 2CH3 of N(i-Pr2)),
3.33–3.39 (m, 1H, NCH), 3.69 (s, 3H, OCH3), 3.75–3.82
(m, 1H, NCH), 6.70 (s, 1H, CH-3) ppm; 13C NMR
(100 MHz, CDCl3): d = 19.94, 20.51, 45.63, 50.52, 53.02,
1
Yellowish liquid, yield 56%; H NMR (400 MHz, CDCl3):
d = 0.65 (d, J = 6.8 Hz, 3H, CH3-12), 0.74–0.81 (m, 7H,
CH-13, CH3-14, CH3-15), 0.92–1.02(m, 2H, CH2-9), 1.09 (d,
J = 5.6 Hz, 6H, 2CH3 of N(i-Pr2)), 1.35 (d, J = 6.8 Hz, 6H,
2CH3 of N(i-Pr2)), 1.37–1.39 (m, 2H, CH-8, CH-11),
1.56–1.60 (m, 2H, CH2-10), 1.79–1.95 (m, 2H, CH2-7),
3.36–3.44 (m, 1H, NCH), 3.78–3.85 (m, 1H, NCH),
4.67–4.75 (ddd, J1 = 4.4 Hz, J2 = 4.0 Hz, J3 = 4.4 Hz,
1H, CH-6), 6.62 (s, 1H, CH-5) ppm; 13C NMR (100 MHz,
CDCl3): d = 15.96, 20.07, 20.20, 20.60, 20.64, 20.69, 21.90,
23.04, 25.80, 31.31, 34.02, 40.12, 45.64, 46.74, 50.39, 76.88,
ꢀ
125.83, 135.35, 161.75, 162.88 ppm; IR (KBr): m = 3,016,
2,970, 2,929, 1,730, 1,632, 1,438, 1,342, 1,245, 1,026,
971, 770 cm-1; UV (CH2Cl2): kmax = 266 nm; ESI–MS:
m/z = 248 ([M ? H]?, 100).
Crystal cultivation and structure determination
X-ray single crystal diffraction was determined on a Bruker
AXS SMART 1000 CCD diffractometer equipped with a
ꢀ
126.82, 134.59, 160.91, 162.86 ppm; IR (KBr): m = 2,957,
123

452
Y.-Q. Mo et al.
Biological activity assay of compounds 2–7
graphite monochromator at 296(2) K using Mo Ka radia-
tion (k = 0.071073 nm). The structures were solved by
direct methods. Most of the non-hydrogen atoms were
located from an E-map. The coordinates of remaining non-
hydrogen atoms as well as some hydrogen atoms were
found by difference Fourier techniques. The structures
were refined by the full-matrix least-squares method with
anisotropic thermal parameters for all non-hydrogen atoms
and isotropic thermal parameters for hydrogen atoms. All
calculations were performed with the SHELXL-97 pro-
gram [65–68].
According to the literature [64], the biological activity
assay of compounds 2–7 was preliminarily investigated by
the MTT method on A549 cells in vitro.
Acknowledgements The authors are grateful to the National Nat-
ural Science Foundation of China (no. 20772035) and the Natural
Science Foundation of Guangdong Province (no. 5300082) for the
financial support of this work. We also thank Dr. Guo-Liang Li and
Dr. Li-Ming Fang for helpful discussions.
Compound 2h was dissolved in a mixture of ethanol and
diethyl ether. A colorless monocrystal was separated from the
solution at room temperature after standing for several days.
Compound 2h, C20H34ClNO3, Mr = 371.93, is attributed to
the tetragonal system and P41 space group. The crystal lattice
parameters are a = 1.3554(19) nm, b = 1.3554(19) nm,
c = 1.1926(17) nm, V = 2.1909(5) nm3, Z = 4, Dc =
1.128 Mg/m3, l = 0.191 mm-1, F(000) = 808. A total of
3,914 reflections together with 3,945 independent ones
(Rint = 0.0000) were collected in the range of
1.5 B h B 25.20° by using the u–x scan mode at room
temperature, in which 3,732 reflections (I C 2r(I)) were
observed and used in the succeeding refinements. The final
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3
˚
Flack parameter is 0.03(4), (Dq)max = 0.237 e/A ,
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3
3
˚
˚
(Dq)max = 0.185 e/A , (Dq)min = -0.269 e/A , S = 1.043,
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Atomic coordinates, bond lengths, bond angles, and
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Crystallographic Data Centre (CCDC) and allocated the
deposition numbers CCDC 787814 (2h) and 787815 (3b).
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