Selective amination of the mucohalic acid derivatives

Article abstract of DOI:10.1016/j.cclet.2013.01.035

An efficient synthesis of 4,5-diamino-3-halofuran-2(5H)-ones has been developed based on a sequential acylation and bisamination of mucohalic acids. The β- and γ-amination products have also been prepared with high regioselectivity. This reaction shows some advantages in terms of its simple operation and readily available but highly functionalized starting material. All products gave satisfactory IR, ¹H NMR, ¹³C NMR and HRMS.

Full text of DOI:10.1016/j.cclet.2013.01.035

G Model
CCLET-2449; No. of Pages 3
Chinese Chemical Letters xxx (2013) xxx–xxx
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Chinese Chemical Letters
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Original article
Selective amination of the mucohalic acid derivatives
a
Tian-Cai Li a, Cou-Xi Chen a, Xue-Qiang Li a,b, , Xiao-Hui Gao
*
a School of Chemistry and Chemical Engineering, Ningxia University, Yinchuan 750021, China
b Ningxia Development Center of Natural Products and Medication, Ningxia University, Yinchuan 750021, China
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient synthesis of 4,5-diamino-3-halofuran-2(5H)-ones has been developed based on a sequential
Received 9 November 2012
Received in revised form 19 December 2012
Accepted 5 January 2013
Available online xxx
acylation and bisamination of mucohalic acids. The
b- and g-amination products have also been
prepared with high regioselectivity. This reaction shows some advantages in terms of its simple
operation and readily available but highly functionalized starting material. All products gave satisfactory
IR, 1H NMR, 13C NMR and HRMS.
ß 2013 Xue-Qiang Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Keywords:
4,5-Diamino-3-halofuran-2(5H)-ones
2(5H)-Furanones
Amine
Selective amination
1. Introduction
diamination process of mucohalic acid derivatives to afford 4, 5-
diamino-3-halofuran-2(5H)-ones (Scheme 2).
Butenolides [2(5H)-furanones] are an important class of
compounds, because the butenolide motifs are found in many
complex natural products and pharmaceutical intermediates [1].
For example, 5-hydroxyfuran-2(5H)-ones have shown activity as
antimutagen, bactericides, antitumor agents, allergy inhibitors,
stimulatory agents, cyclooxygenase inhibitors, phospholipase A2
inhibitors, etc. [2]. Despite these achievements, the development of
efficient and convenient methods for the synthesis of highly
functionalized butenolides for further elaboration is still of current
interest.
Recently, 3,4-dihalo-5-hydroxy-2(5H)-furanones (mucohalic
acids) have attracted considerable attention due to their unique
disposition of various functionalities [3]. According to the
literature, those inexpensive, commercially available materials
can be easily transformed to various substituted butenolides in the
presence of different nucleophilic reagents via three different
pathways (Scheme 1): (a) via a Michael addition-elimination
process at the vinylogous position to afford compound 2. (b) via an
2. Experimental
A represent procedure for the amination of the mucohalic acid
derivatives with amines is presented as following:
To a stirred solution of 5-acetoxy-3,4-dihalo-5H-furan-2-one 1
(1 mmol) in toluene (20 mL) was added excess of amine 6 at 20–
30 8C. After an additional 1.5 h (monitored by TLC), The resulting
mixture was poured into ice water (10 mL) and toluene (20 mL),
the organic layers were dried over anhydrous Mg2SO4, and
evaporated under reduced pressure. The residue was purified by
silica gel column chromatography eluting with petroleum ether–
EtOAc (4:1) to give the target product 5k: Light-yellow solid, mp
116–118 8C, yield 46%.1H NMR (400 MHz, CDCl3):
3.14 (s, 3H), 3.84 (m, 2H), 4.67 (m, 2H), 5.49 (s, 1H), 7.17–7.38 (m,
10H); 13C NMR (100 MHz, CDCl3):
169.46, 158.66, 136.80, 136.01,
127.29–129.23, 91.21, 87.90, 74.25, 55.59, 38.62 29.70; IR (KBr,
cmꢀ1):
max: 2935, 1731, 1614, 1456, 1319, 1114, 732. ESI-TOFMS
d 2.33 (s, 3H),
d
n
SN2 process at the allyl position to give the
g
-substituted product 3.
m/z: 401. 0865 [M+H]+, calcd. for C20H22BrN2 O2: 401.0865.
(c) via an SN20 process to form compound 4.
However, only one molecular nucleophile participated in those
reactions described above. There are no reports on such a process
3. Results and discussion
occurring at both the vinylogous and allyl positions to furnish
b
,
g
-
Recently, Zhang et al. [4] reported an efficient amination
disubstituted product 5A. Herein, we wish to report a successful
process of mucohalic acids 1, but only g-substituted product (via
an SN2 process) was formed even an excess amount of amine was
used. It is very interesting that a favorable Michael addition-
elimination process did not occur. We believed that the two
processes are competitive in this reaction and envisioned that the
* Corresponding author.
E-mail address: lixq@nxu.edu.cn (X.-Q. Li).
1001-8417/$ – see front matter ß 2013 Xue-Qiang Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.01.035
Please cite this article in press as: T.-C. Li, et al., Selective amination of the mucohalic acid derivatives, Chin. Chem. Lett. (2013), http://
dx.doi.org/10.1016/j.cclet.2013.01.035

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CCLET-2449; No. of Pages 3
2
T.-C. Li et al. / Chinese Chemical Letters xxx (2013) xxx–xxx
Table 1
O
Me
Bn
O
O
O
Bisamination of mucohalic acids 1.
Me
HN
N
toluene
r.t.
OCOCH3
Yield (%)a
+
Entry
1
6
T (h)
5
Cl
Cl
Bn
X
R1
R2
Cl
Cl
7a
1
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Br
Br
Cl
H
Me
Et
4
5a
5b
5c
5d
5e
5f
59
58
60
60
48
55
55
58
59
53
46
50
2
H
4
Scheme 3.
g
-Amination of mucochloric ester with secondary benzyl amine.
3
H
n-Pr
n-Bu
Bn
1.5
1.5
1.5
4.5
4
4
H
5
H
6
H
Me
Et
O
O
7
H
5g
5h
5i
O
O
8
H
n-Pr
n-Bu
Me
Bn
1.5
1.5
1
OCOCH3
+
Et
HN
Et
toluene
r.t.
Br
OCOCH3
9
H
Br
10
11
12
Me
Me
Me
5j
N
Br
Et
Et
1.5
1
5k
5l
Me
8a
a
O
Isolated yields.
O
O
Et
N
Et
O
Et
HN
Et
OCOCH3
+
toluene
r.t.
Cl
Cl
Cl
bisamination product could form by a careful choice of amines and
conditions. The starting material 1 was prepared readily by the
acylation of the hydroxy group in mucohalic acid in the presence of
a solid acid catalyst [5]. To our delight, mucohalic acid acetates 1
reacted with some selected amines in toluene at room temperature
Cl
7b
Scheme 4. Different regioselectivities of the aminations of mucobromo ester and
mucochloric ester.
affording a series of
b, g-disubstitution products 5 in moderate to
good yields (Table 1). Treatment mucobromo or mucochloric esters
with selected primary amines gave the corresponding
bisamination products
mucobromo acid acetate reacted with benzylamine gave
diamination product 5e in 48% yield in a short period of time,
which is different from Zhang’s report (entry 5) [4]. For less
hindered dimethylamine, both mucobromo and mucochloric acid
b
,
g
g
-
Presumably these differences were caused by nucleophilic
reagents steric effects.To compare the difference between muco-
bromo and mucochloric acid acetate in reactivity, they were both
treated with diethylamine. Surprisingly, the mucochloric deriva-
5
in good yields (entries 1–9). The
b
,
-
tive gave the
g
-amination product 7b in 70% yield. However, the
-amination product 8a in
mucobromo acid acetate afforded the
b
acetates can be converted to
yields (entry 10 and 12). When N-methylbenzylamine was used,
the mucobromo acid acetate gave -diamination product 5k in
46% yield, while the mucochloric acid acetate only afforded
amination product 7a in 68% yield. (entry 11 and Scheme 3).
b
,
g
-diamino products 5 in moderate
75% yield (Scheme 4). We thought this is due to the difference of
the C–X bond energy. The results indicated that the regioselectivity
of the substitution reaction could be more easily controlled by
choosing the suitable mucohalo acid derivatives and amine by
comparison with Klaus’s report [6].
b, g
g
-
4. Conclusion
O
X
R
O
O
In conclusion, we have reported an efficient synthesis of various
4,5-diamino-3-halofuran-2(5H)-ones, and disclosed an interesting
way to control the regioselectivity of amination of the mucohalo
acid derivatives. Further investigations on the mechanistic study
and extension of the scope of these reactions are under way in our
group.
a
Nu
2
3
O
X
R
O
O
O
O
b
Nu
NuH
+
X
O
X
X
X
Acknowledgments
c
1
O
We are grateful for the financial support by the National Natural
Science Foundation of China (No. 21062014), the Key Project of
Chinese Ministry of Education (No. 210237), the Key Laboratory of
Medicinal Chemistry for Natural Resource, Yunnan University (No.
200902205), and the Leading Academic Discipline Program of 211
Project of Ningxia University (the 3rd phase).
Nu
X
O
X
O
4
Nu
Nu
5A
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Please cite this article in press as: T.-C. Li, et al., Selective amination of the mucohalic acid derivatives, Chin. Chem. Lett. (2013), http://
dx.doi.org/10.1016/j.cclet.2013.01.035