A catalyst-free, convenient construction of eight-membered [1,4]oxazocane-5,8-dione heterocycles from aminoethanols with divinyl succinate

Article abstract of DOI:10.1055/s-2008-1078572

A convenient protocol for the synthesis of [1,4]oxazocane-5,8-dione heterocycles by direct cyclization using 2-substituted aminoethanols and divinyl succinate without any catalysts and additives was established. This strategy is quite simple and effective to obtain eight-membered rings incorporating lactone and lactam functional groups. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078572

LETTER
1829
A Catalyst-Free, Convenient Construction of Eight-Membered
[1,4]Oxazocane-5,8-dione Heterocycles from Aminoethanols with Divinyl
Succinate
E
ight-Membered[1,4]O
a
xazocane-5
n
,8-dione He
t
-
erocycle
Q
s
in Chen, Qing-Yi Zhang, Bo-Kai Liu, Qi Wu, Xian-Fu Lin*
Department of Chemistry, Zhejiang University, Hangzhou, 310027, P. R. of China
Fax +86(571)87952618; E-mail: llc123@zju.edu.cn
Received 25 March 2008
venient route for obtaining functionalized [1,4]oxazo-
cane-5,8-dione heterocycles in moderate to high yields.
Abstract: A convenient protocol for the synthesis of [1,4]oxazo-
cane-5,8-dione heterocycles by direct cyclization using 2-substitut-
ed aminoethanols and divinyl succinate without any catalysts and
additives was established. This strategy is quite simple and effective
to obtain eight-membered rings incorporating lactone and lactam
functional groups.
The starting aminoethanol derivatives were easily acces-
sible from commercial amino acids using NaBH4 and I2
according to the routes previously reported (Scheme 1).16
The pure aminoethanol analogues were obtained in yields
ranging from 78% to 86% after purification by column
chromatography.
Key words: aminoethanol, divinyl succinate, catalyst-free,
[1,4]oxazocane-5,8-dione, cyclization
NH2
NH2
NaBH4, I2
OH
The preparation of medium-sized heterocycles has attract-
ed much attention due to their wide applications such as
biologically active natural products,1 drug candidates,2
materials,3 and catalyst.4 For example, many eight-mem-
bered heterocycles are very common in submarine
species5 or in drugs.6 Approaches for the synthesis of
eight-membered heterocycles were mostly available
based on ring expansion,7 ring-closing metathesis,8 trans-
annular cyclizations,9 and metal-mediated ring cycliza-
tion.10 However, the convenient construction of these
heterocycles incorporating one or more heteroatoms re-
mains a synthetic challenge for organic chemists.11
OH
R
THF, reflux
R
O
2a–j
1a–j
Scheme 1 Reduction of amino acids. Reagents and conditions:
NaBH4, I2, THF, reflux.
O
O
O
NH2
O
OH
+
O
HN
O
O
Eight-membered [1,4]oxazocane-5,8-dione heterocycles
bearing oxazocane functional group are important inter-
mediates of natural products12 and expected to possess po-
tent biological activities such as NK1 antagonists and
non-narcotic analgesic drugs.13 To date, a few approaches
for the construction of the [1,4]oxazocane-5,8-dione het-
erocycles have been established. Aly14 reported a strategy
involving reaction of diethyl phthalate with N-tosyl-2-
aminophenol derivatives to generate [1,4]oxazocane-5,8-
dione heterocycles. Assoumatine and co-workers12 report-
ed analogous reactions of a succinate diester with amino
alcohol derivatives through a multiple and complex pro-
cess. Banfi and co-workers15 transformed pyrroline deriv-
atives into 2,5-functionalized pyrrolidines, which allowed
an access to medium-sized bicyclic heterocycles by lac-
tonization. However, no literature for the synthesis of me-
dium-sized ring systems by simply direct cyclization
reactions without any catalyst has been reported. Herein,
we prepared a series of eight-membered heterocycles via
catalyst-free cyclization reaction, which provided a con-
2a
3
4a
Scheme 2 Reaction of 2-amino-2-methyl-1-propanol with divinyl
succinate
The reaction of 2-amino-2-methyl-1-propanol (2a) with
divinyl succinate (3) was investigated in DMSO at 110 °C
without any catalyst and additive (Scheme 2). The expect-
ed product was obtained after four hours and was charac-
terized by H NMR, 13C NMR, IR, ESI-MS and two-
1
dimensional NMR techniques (HMQC). The structure
was confirmed as an eight-membered heterocycle 3,3-
dimethyl-[1,4]oxazocane-5,8-dione (4a).17
The reaction conditions were optimized using 2-amino-2-
methyl-1-propanol (2a) as a model substrate (Scheme 2).
Solvent often plays an important role in the reaction due
to their different polarity and solubility of the reactant or
product. Six conventional organic solvents were screened
for the reaction of 2a with divinyl succinate. The results
(Figure 1) showed that highly polar solvents (DMSO and
DMF), which enhanced the nucleophilicity of 2a by hy-
drogen bond formation with the polar solvent,18 efficient-
ly promoted the reaction and a moderate yield of 4a was
obtained. In contrast, less polar or nonpolar solvents such
SYNLETT 2008, No. 12, pp 1829–1832
x
x
.x
x
.2
0
0
8
Advanced online publication: 02.07.2008
DOI: 10.1055/s-2008-1078572; Art ID: W04908ST
© Georg Thieme Verlag Stuttgart · New York

1830
W.-Q. Chen et al.
LETTER
Figure 1 Influence of organic solvents on the yield of 2-amino-2-
methyl-1-propanol with divinyl succinate. Reagents and conditions:
2-amino-2-methyl-1-propanol (2.5 mmol), divinyl succinate (3.0
mmol), organic solvent (5 mL), 80 °C, 6 h.
Figure 3 Time course of the reaction of 2-amino-2-methyl-1-pro-
panol and divinyl succinate. Reagents and conditions: 2-amino-2-
methyl-1-propanol (2.5 mmol), divinyl succinate (3.0 mmol), DMSO
(5 mL).
that amines are more active than alcohols as nucleophiles.
In fact, only the chain compound of N-acylation was de-
tected and no chain product of O-acylation was observed
during the reaction. Then the chain compound of N-acyl-
ation was followed by an intramolecular O-acylation reac-
tion and transformed into cycloproduct 3,3-dimethyl-
[1,4]oxazocane-5,8-dione (4a). The reaction reached
equilibrium after four hours with 78% yield.
as acetonitrile, dioxane, benzene, and toluene resulted in
poor yields of 4a. Therefore, DMSO was selected as sol-
vent for the following reaction.
The influence of temperature on the reaction was investi-
gated. The results are shown in Figure 2. When 2a was
treated with divinyl succinate in DMSO at different tem-
perature ranged from 60 °C to 110 °C for two hours, the
yield of 4a increased from 28% to 55% (HPLC). When
the temperature increased from 110 °C to 140 °C, there
was no obvious influence on the yield. It showed that the
reaction proceeded efficiently at 110 °C.
Table 1 Reaction of 2-Substituted Aminoethanol Derivatives with
Divinyl Succinate in DMSOa
O
O
O
NH2
DMSO
110 °C
O
OH
+
O
R
R
N
H
O
O
4a–k
2a–k
Entry Substrate 219
Product 4
Yield (%)b
O
O
O
1
2
3
OH
73 (4a)
NH2
N
H
O
O
O
OH
77 (4b)
67 (4c)
NH2
HN
Figure 2 Influence of temperature on the yield of 2-amino-2-
methyl-1-propanol with divinyl succinate. Reagents and conditions:
2-amino-2-methyl-1-propanol (2.5 mmol), divinyl succinate (3.0
mmol), DMSO (5 mL).
O
O
Cl
OH
NH2
Cl
HN
The time course of the reaction was also investigated. As
shown in Figure 3, the whole reaction consisted of two
steps, the N-acylation and O-acylation. It is well known
O
Synlett 2008, No. 12, 1829–1832 © Thieme Stuttgart · New York

LETTER
Eight-Membered [1,4]Oxazocane-5,8-dione Heterocycles
1831
Table 1 Reaction of 2-Substituted Aminoethanol Derivatives with
Next, the influence of chain length of divinyl dicarboxy-
lates and the different diester dicarboxylates on the ring
closure reaction with 2a under identical reaction condi-
tions was examined. Three divinyl dicarboxylates includ-
ing divinyl succinate, divinyl adipate, and divinyl
sebacate were investigated. Only divinyl succinate afford-
ed the cycloproduct after four hours, while chain com-
pounds of N-acylation were observed from the reaction
between the other two divinyl dicarboxylates and 2a after
six hours. Furthermore, two diester dicarboxylates, di-
methyl succinate and dimethyl adipate, were tested. After
24 hours no product was detected. The results showed that
divinyl dicarboxylates and diester dicarboxylates with
longer chains were unfavorable for the direct ring-closure
reaction.
Divinyl Succinate in DMSOa (continued)
O
O
O
NH2
DMSO
O
OH
+
O
R
110 °C
R
N
O
H
O
4a–k
2a–k
Entry Substrate 219
Product 4
Yield (%)b
O
O
OH
NH2
4
68 (4d)
HN
O
We then examined the generality of these conditions to
other substrates. Results were summarized in Table 1. The
reactions of three aromatic substituted aminoethanols
with divinyl succinate were examined (entries 2–4,
Table 1). 2-Benzyl aminoethanol generated the 3-benzyl-
[1,4]oxazocane-5,8-dione in 77% yield. Compared with
2-benzyl aminoethanol, 2-(4-chlorobenzyl) aminoethanol
showed lower reactivity than divinyl succinate in 67%
yield. It demonstrated that the electron-withdrawing ef-
fect had influence on the reaction. A similar observation
was obtained from 2-phenyl aminoethanol. We then ex-
amined the reactions of different aliphatic substituted
aminoethanols. The yields ranged from 69% to 78% (en-
tries 5–9). The different aliphatic substituted groups play
a minimal role in the yields of the reactions. The 2-amino-
4-methylsulfanyl-butan-1-ol also could generate 3-(2-
O
O
O
OH
5
6
7
8
75 (4e)
78 (4f)
69 (4g)
75 (4h)
NH2
HN
O
O
OH
NH2
HN
O
O
O
OH
NH2
HN
O
O
methylsulfanylethyl)-[1,4]oxazocane-5,8-dione
(entry
10) with high yield of 83%. The results showed that this
protocol proved to be effective to form the [1,4]oxazo-
cane-5,8-dione scaffolds from different substrated amino-
ethanols.
O
OH
NH2
N
H
O
In summary, an efficient and convenient method for syn-
thesis of eight-membered [1,4]oxazocane-5,8-dione de-
rivatives was established. It is noteworthy that the
procedure does not require any catalyst and can be effi-
ciently achieved via a simply direct cyclization. This
study is of significance in the synthesis of the interesting
family of [1,4]oxazocane-5,8-dione scaffolds.
O
O
O
OH
NH2
9
72 (4i)
N
H
O
O
O
S
OH
10
11
83 (4j)
61 (4k)
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
NH2
S
N
H
O
O
References and Notes
OH
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Synlett 2008, No. 12, 1829–1832 © Thieme Stuttgart · New York

1832
W.-Q. Chen et al.
LETTER
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2-Amino-2-methyl-1-propanol (20 mmol) was dissolved in
DMSO (20 mL) and the divinyl succinate (24 mmol) was
added. The reaction mixture was stirred at 110 °C and
monitored by TLC. Upon completion of the reaction, the
reaction gave a yellow solution which was purified by
column chromatography (hexane–EtOAc, 1:1) to obtain the
product. 1H NMR (500 MHz, CDCl3): d = 3.81 (d, 2 H,
J = 5.6 Hz), 3.57 (br s, 1 H), 2.66 (s, 4 H), 1.48 (s, 6 H) ppm.
13C NMR (100 MHz, CDCl3): d = 179.2, 69.2, 62.8, 28.6,
22.1 ppm. ESI-MS: m/z = 193.8 [M + Na]+. IR: 3440 (NH
amide), 1772 (C=O amide), 1696 (C=O ester) cm–1.
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