Facile Syntheses of Azetidin-3-ols by Rearrangement of 2,3-Epoxypropylamines

Article abstract of DOI:10.1081/SCC-120026859

The N-alkyl-2,3-epoxypropylamines (2) formed from primary alkylamines (1) and epichlorohydrin were chemoselectively rearranged to the four-membered rings, N-alkylazetidin-3-ols (3), upon treatment of triethylamine in refluxing acetonitrile.

Full text of DOI:10.1081/SCC-120026859

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Facile Syntheses of Azetidin-3-ols by Rearrangement of
2
,3-Epoxypropylamines
a
a
a
b
Associate Professor Chang Ho Oh , Chul Yun Rhim , Choong Ho You & Jin Rai Cho
a
Department of Chemistry, Hanyang University, Sungdong-Gu, Seoul, South Korea
b
Agency for Defence Development, Yuseong, Taejon, Korea
Version of record first published: 21 Aug 2006
To cite this article: Associate Professor Chang Ho Oh, Chul Yun Rhim, Choong Ho You & Jin Rai Cho (2003): Facile Syntheses
of Azetidin-3-ols by Rearrangement of 2,3-Epoxypropylamines, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:24, 4297-4302
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 24, pp. 4297–4302, 2003
Facile Syntheses of Azetidin-3-ols by
Rearrangement of 2,3-Epoxypropylamines
1
,
1
1
Chang Ho Oh, * Chul Yun Rhim, Choong Ho You,
2
and Jin Rai Cho
1
Department of Chemistry, Hanyang University,
Sungdong-Gu, Seoul, South Korea
2
Agency for Defence Development,
Yuseong, Taejon, Korea
ABSTRACT
The N-alkyl-2,3-epoxypropylamines (2) formed from primary alkyl-
amines (1) and epichlorohydrin were chemoselectively rearranged to
the four-membered rings, N-alkylazetidin-3-ols (3), upon treatment
of triethylamine in refluxing acetonitrile.
Polynitrated small-size heterocycles and carbocycles are at the
forefront of the search for more powerful and less sensitive energetic
materials because of the increased performance expected from the
additional energy increase upon opening of the strained ring system
*
Correspondence: Chang Ho Oh, Associate Professor, Department of Chemistry,
Hanyang University, Sungdong-Gu, Seoul 133-791, South Korea; E-mail:
changho@hanyang.ac.kr.
4
297
DOI: 10.1081/SCC-120026859
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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4
298
Oh et al.
during decomposition. An important new member of this class of
energetic materials is 1,3,3-trinitroazetidine (TNAZ), a potentially
ꢀ
melt castable explosive has
ꢁ
a
moderate density (1.84 gcm ), good thermal stability (>240 C), and
melting point (m.p. 110 C),
ꢀ
3
[1]
low sensitivity. The principal source of 1,3,3-trinitroazetidine remains
the original preparative method starting from tert-butylamine and
[2]
epichlorohydrin.
We have initiated preparation of polymer-bound polynitroazetidines
as new energetic materials and hence needed sterically nonbulky
N-alkylazetidin-3-ols. Although Gaertner’s preparation of azetidinols
from epichlorohydrin was limited to sterically hindered amines, some
important progress has been made toward more productive synthesis of
[
3]
these compounds.
reaction time for ring-closure and increased the yield of products
Okutani et al. substantially decreased the
[
conducting the reactions in acetonitrile and Gaj reported a modified
4]
synthetic method for N-alkylazetidin-3-ols from sterically less hindered
[
5]
amines and methoxymethyl ethers of 1,3-dichloro-2-propanols. Jenkins
and Higgins successively reported improved method for preparation of
[
6]
the ether derivatives of azetidinols with nonbulky N-alkyl substituents.
In searching for the more convenient methods for preparation of
3-azetidinols, the rearrangement of N-alkyl-2,3-epoxypropylamines (2)
was investigated. The 2,3-epoxyamines (2) were prepared from
epichlorohydrin and various amines according to the known methods
as summarized in Table 1.
A solution of the primary amines 1 and epichlorohydrin in
isopropanol was stirred for about 24 h to give the N-alkyl-2,3-epoxy-
propylamines 2a–g without contaminating the corresponding tertiary
amines.
Intramolecular cyclization of 2,3-epoxyamines 2 can lead to
azetidin-3-ols (3) by nucleophilic attack at the terminal C-3 carbon or
to hydroxymethylaziridines 4 as known as the aza-Payne rearrangement
via a 3-exo-tet type pathway (Eq. (1)).
OH
OH
R
O
Et3N
N
H
+
CH3CN, reflux
ð1Þ
N
R
3
N
R
4
1
2-24 h
2
Recently, Karikomi et al. found that magnesium bromide
could be of great utility for the regioselective rearrangement of
[
,3-epoxyamines to N-alkyl-3-azetidinols. During our preparation of
7]
2

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Facile Syntheses of Azetidin-3-ols
Table 1. Preparations of N-alkyl-2,3-epoxyamines.
4299
R
O
i-PrOH
RT, 4 - 24 h
N
H
Cl
+
RNH
2
O
1
2
Entry
R group
Time (h)
Products
Yield (%)
1
2
3
4
5
6
7
t-Butyl-
Isopropyl-
24
24
16
6
2a
2b
2c
2d
2e
2f
98
94
90
86
81
81
98
n-Butyl-
HOCH
Allyl-
2 2
CH -
24
24
24
Benzyl-
Diphenylmethyl-
2g
Table 2. Cyclizations of N-alkyl-2,3-epoxypropylamine hydrochlorides (2) to
N-alkylazetidin-3-ols (3).
Entry
R group
t-Butyl-
Isopropyl-
Time (h)
Products
Yield (%)
1
2
3
4
5
6
7
16
17
22
12
24
24
24
3a
3b
3c
3d
3e
3f
85
47
40
26
50
56
72
n-Butyl-
HOCH
Allyl-
2 2
CH -
Benzyl-
Diphenylmethyl-
3g
N-tert-butylazetidin-3-ol, we found that treatment of triethylamine to N-
tert-butyl-2,3-epoxypropylamine 2a in acetonitrile was rearranged to the
corresponding azetidinol 3a in highly efficient manner. Then, we have
optimized the reaction conditions applicable to preparation of
various alkyl-substituted 3-azetidinols 3b–3g. When these 2,3-epoxy-
amines were refluxed in acetonitrile in the presence of triethylamine as
a base, they were smoothly cyclized to the N-alkylazetidin-3-ols in good
yields as summarized in Table 2.
Several features are to be noted. First, the present method allows for
the control of chemoselective rearrangement of 2,3-epoxypropylamines
to azetidin-3-ols (3) without using magnesium bromide. Second, simple
modification of the known reaction conditions has shown to be
applicable to synthesis of various N-alkyl-azetidin-3-ols from sterically
nonhindered amines. Especially, triethylamine might help the nucleo-

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300
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Facile Syntheses of Azetidin-3-ols
4301
philic nitrogen of 2,3-epoxypropylamines attack to the epoxide at the less
hindered end. In summary, this facile azetidinol synthesis could be a good
method for nonbulky alkyl-substituted azetidin-3-ols (3).
GENERAL EXPERIMENTAL
1
. General Procedure
All reactions were performed under an atmosphere of dry argon.
Commercial reagents were used as received without further purification.
All products were purified by flash column chromatography using silica
gel 60 (79–230 mesh, Merck). The purified products were identified with
1
13
H and C NMR spectral data obtained from a Varian Mercury
00 MHz NMR spectrometer using tetramethylsilane as an internal
standard.
4
2. A Typical Procedure for Synthesis of
N-Alkyl-2,3-epoxyamines 2
To a solution of diphenylmethylamine (1g, 1.00 g, 5.46 mmol) in
isopropylalcohol (10 mL) was added dropwise epichlorohydrine (430 mL,
ꢀ
5
.46 mmol) at 0 C. Then, this mixture was stirred at RT for 24 h,
concentrated under reduced pressure and the residue was purified by
flash column chromatography on silica gel (hexane/ethyl acetate ¼ 10/1)
to give N-diphenylmethyl-2,3-epoxypropylamine 2g (1.28 g, 98% yield).
3. A Typical Procedure for Synthesis of
N-Alkylazetidin-3-ols 3
To a solution of N-diphenylmethyl 2-3-epoxypropylamine (2g, 1.30 g,
.43 mmol) in acetonitrile (10 mL) was added triethylamine (2.3 mL,
6.3 mmol) at 0 C. Then, this mixture was refluxed for 24 h, cooled to
5
1
ꢀ
room temperature. The solution was concentrated under reduced
pressure and the residue was purified by flash column chromatography
in silica gel (hexane/ethyl acetate ¼ 2/1) to give a N-diphenylmethyl-
azetidin-3-ol (3g, 0.93 g, 3.91 mmol, 72% yield) as a white solid. M.p.:
ꢀ
[2b]
ꢀ
1
13
110–113 C (Lit.
tabulated in Table 3.
113 C). H NMR and C NMR data for 3a–g are

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ACKNOWLEDGMENTS
We wish to acknowledge the financial support of Agency for Defence
Development (ADD-01-8-001), Korea.
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7
3
1
Received in the UK July 24, 2003