Microwave-assisted synthesis of azetidines in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2009.09.063

Simple azetidines are synthesized in good to excellent yields and high purity via cyclization of 3-(ammo-nio)propyl sulfates derived from primary amines and the cyclic sulfate of 1,3-propanediol. A feature of this methodology includes the accelerated synt

Full text of DOI:10.1016/j.tetlet.2009.09.063

Tetrahedron Letters 50 (2009) 6590–6592
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Tetrahedron Letters
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Microwave-assisted synthesis of azetidines in aqueous media
b
a
a
Brendan A. Burkett a, , Samuel Z. Ting , Gwendolyn C. S. Gan , Christina L. L. Chai
*
a New Synthesis Techniques and Applications, Institute of Chemical and Engineering Sciences, A*STAR, 1 Pesek Road, Jurong Island, Singapore 627833, Singapore
b School of Chemical and Physical Sciences, Victoria University of Wellington, Wellington, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
Simple azetidines are synthesized in good to excellent yields and high purity via cyclization of 3-(ammo-
nio)propyl sulfates derived from primary amines and the cyclic sulfate of 1,3-propanediol. A feature of
this methodology includes the accelerated synthesis of azetidines in water under the influence of micro-
wave-assisted heating.
Received 9 August 2009
Revised 2 September 2009
Accepted 11 September 2009
Available online 15 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Azetidines
Microwaves
Cyclization
Cyclic sulfates
Green chemistry
Azetidines (1) are heterocycles of enormous interest owing to
their wide and varied applications. Azetidines and azetidine-con-
taining structures are well known not only for their biological
activities,1 but also for their usefulness as monomers and cross-
linkers in the polymer industry2 and as valuable synthetic interme-
diates in their own right.3 Traditional methods of accessing azeti-
were therefore intrigued to investigate whether the superior heat-
ing offered by modern microwave reactors could be exploited to
improve the yields in our proposed synthesis.
A range of 3-(N-substituted ammonio)propyl sulfates (2a–i)
were synthesized in excellent yields following reaction of a variety
of primary amines with 3 in acetonitrile (Scheme 2). An attractive
feature of the preparation is the fact that the zwitterionic ammo-
nium sulfates precipitate from the reaction mixture allowing most
of the products to be obtained analytically pure following filtration
of the crude reaction mixture (Table 1).
dines include the cyclization of suitably activated
c-amino
alcohols,4,5 -amino halides5a,6 and - and b-haloimines.7 Whilst
c
x
some of these methods result in problematic elimination, dimer-
ization or fragmentation,5g other methods8 tend to be less applica-
ble for general use. We report here an alternative and efficient
methodology for accessing simple azetidines through cyclization
of 3-(N-alkylamino)propyl sulfates (2) furnished from the reaction
of primary amines with the cyclic sulfate of 1,3-propanediol (3)
(Scheme 1).
The use of 3 as the source of the azetidine backbone is advanta-
geous as the zwitterionic 3-(N-substituted ammonio)propyl sul-
fates would avoid problems associated with dialkylation and
oligomerization commonly encountered in azetidine synthesis
employing 1,3-dihalopropanes or bis-activated diols as alkylating
agents. In addition, the use of 3 provides an expedient method of
accessing activated 3-amino alcohols in a single step without
requiring the handling of air/moisture-sensitive reagents.
Whilst the base-mediated thermal cyclization of 3-(N-substi-
tuted ammonio)propyl sulfates is low yielding,5a microwave-as-
sisted synthesis of N-phenylazetidine from aniline and 1,3-
dichloropropane has been reported to proceed in good yield.9 We
O
O
S
O
O
R
H
R
N
O3SO
N
3
+
H
2
1
RNH2
Scheme 1. Synthetic strategy for the synthesis of simple azetidines.
O
O
H
H
S
80 ºC
OSO3
N
O
O
RNH2
+
R
MeCN
90 min
3
2
* Corresponding author.
Scheme 2. Synthesis of 3-(N-substituted ammonio)propyl sulfates 2.
E-mail address: brendan_burkett@ices.a-star.edu.sg (B.A. Burkett).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.063

B. A. Burkett et al. / Tetrahedron Letters 50 (2009) 6590–6592
6591
Table 1
Isolated yields of 2a–i
H
H
R N
1a-i
OSO3
N
KOH
R
Entry
R
Product
Yield (%)
H2O, MW
150 ºC, 15 min
2a-i
1
2
3
4
5
6
7
8
9
Bn
2a
2b
2c
2d
2e
2f
2g
2h
2i
91
77
88
72
89
83
86
80a
84
n-C6H13
n-C12H25
i-Pr
Scheme 3. Preparation of azetidines 1a–i.
t-Bu
Cyclopentyl
Cyclohexyl
Ph
Table 3
Isolated yields of azetidines 1a–i
Allyl
Entry
R
Product
Yield
a
Estimated 90–95% purity by 1H NMR spectroscopy.
1
2
3
4
5
6
7
8
9
Bn
1a
1b
1c
1d
1e
1f
1g
1h
1i
74
73
79
55
57
84
79
n-C6H13
n-C12H25
i-Pr
Sulfate 2a was then used as a model system to establish optimal
conditions for the cyclization reaction (Table 2). Heating at 120 °C
for 15 min resulted in only trace amounts of 1a being detected (en-
try 1) and increasing the temperature to 150 °C improved this con-
version to 10% (entry 2), however, extending the reaction time led
to decomposition of the products. Addition of 0.2% water had no ef-
fect on the product distribution (entry 3) and a gradual increase in
the amount of water to 50% (entry 4) had an improvement in the
recovery of mass balance, but also resulted in the increased forma-
tion of by-products.
t-Bu
Cyclopentyl
Cyclohexyl
Ph
67a
Traceb
Allyl
74% mass balance, 90% purity (1H NMR).
20% of mass balance recovered as the oligomer.
a
b
nated 2i followed by hydrolysis of the terminal sulfate moiety.
Alternatively, ring-opening oligomerization of the initially formed
N-allyl azetidine could occur, initiated by nucleophilic attack by
hydroxide on the azetidine ring. Variation of the reaction temper-
ature and time did not prevent oligomerization and this anomalous
result was not investigated further.
When a completely aqueous system was utilized, 1a was iso-
lated cleanly and in excellent yield (entry 5) following work-up.
Subsequent experiments focused on establishing the minimum
temperature required for successful conversion of 2a into 1a (en-
tries 6–9). It can clearly be seen that reactions conducted at
100 °C and below resulted in inferior yields or no reaction at all.
Similar low yields were noted for the reaction carried out in boiling
water (entry 10) using conventional heating. In contrast, reactions
carried out at 120 and 150 °C for 15 min gave moderate to good
yields of 1a, although the yield dropped when the reaction time
was reduced to 5 min. The use of LiOH as a base showed some
improvement in the isolated yield of 1a under conventional heat-
ing, but the difference between KOH and LiOH under microwave
conditions was found to be negligible.
Gratifyingly, azetidines 1b–i were obtained reproducibly in
good to excellent yields and in high purity when sulfates 2b–h
were reacted under the optimized conditions (Scheme 3, Table 3).
In the case of 2i it was evident that, in addition to the formation
of minor quantities of 1i, oligomerization had occurred to afford 4
with evidence of n = 1, 2 and 3 detected by ES-MS. This may arise
from direct nucleophilic displacement of the sulfate by deproto-
H
N
N
OH
n
4
Whilst the influence of microwave energy on the cyclization
step was not specifically investigated as part of this study, the sim-
ilar results obtained in experiments at 100 °C under conventional
and microwave heating seem to rule out such an effect. This is par-
ticularly evident when considering the heating data, with reactions
at 100 and 120 °C having almost identical exposure to microwave
energy in the first 5 min of the reaction. We believe that the high
efficiency of microwave heating, the ability to reach temperatures
well above the boiling point of the solvent and the associated in-
crease in internal pressure all contribute favourably to the efficient
cyclization of 2 to azetidines.
Table 2
In summary we have demonstrated an efficient microwave-as-
sisted approach to the synthesis of azetidines starting from 3 and
demonstrated its effective application with a range of structurally
diverse primary amines. Both the synthesis of the zwitterionic
ammonium sulfates 2 and the azetidines proceed in good to excel-
lent yield and produce products of high purity through simple
work-up.
Selected optimization studies for the cyclization of 2a to 1a
Entry
Conditionsa
2a:1a
Yield (1a)
1
2
3
4
5
6
7
8
120 °C, MeCN, 15 min
150 °C, MeCN, 15 min
150 °C, MeCN (+0.2% H2O)
150 °C, 1:1 MeCN/H2O, 15 min
150 °C, H2O, 15 min
120 °C, H2O, 15 min
100 °C, H2O, 15 min
60 °C, H2O, 15 min
1:trace
9:1
9:1
n.d.
0:1
0:1
0:1
NR
0
<5%b
<5%b
<10%b
74%
50%
8%
Acknowledgement
0
9
rt, H2O, 15 min
NR
NR
0:1
0:1
0:1
0
0
41%
9%
71%
10
11
12
13
100 °C, H2O, reflux, 15 minc,d
150 °C, H2O, 5 min
This research was supported by the Science and Engineering Re-
search Council of A*STAR (Agency for Science, Technology and Re-
search), Singapore.
100 °C, H2O, reflux, 15 mind,e
150 °C, H2O, 15 mine
a
All reactions were performed with KOH (2 equiv) under microwave heating
Supplementary data
unless otherwise indicated.
b
Estimated by 1H NMR spectroscopy/mass recovery.
c
Full experimental details, including microwave heating profiles
and spectroscopic data for all compounds. 1H and 13C NMR spectra
for compounds 1a–g and 2a–i are provided. Supplementary data
Impurities detected.
Conventional heating.
d
e
LiOH (2 equiv).

6592
B. A. Burkett et al. / Tetrahedron Letters 50 (2009) 6590–6592
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