Polyethylene glycol (PEG) as an efficient recyclable medium for the synthesis of β-amino sulfides

Article abstract of DOI:10.1016/j.tetlet.2006.01.086

Aziridines undergo ring opening readily with various thiols in the presence of polyethylene glycol (PEG) to afford the corresponding β-amino sulfides in high yields with good regioselectivity under mild and neutral conditions. The PEG can be recovered and

Full text of DOI:10.1016/j.tetlet.2006.01.086

Tetrahedron Letters 47 (2006) 2261–2264
Polyethylene glycol (PEG) as an efficient recyclable medium for
the synthesis of b-amino sulfides
*
Ahmed Kamal, D. Rajasekhar Reddy and Rajendar
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 31 October 2005; revised 4 January 2006; accepted 16 January 2006
Available online 7 February 2006
Abstract—Aziridines undergo ring opening readily with various thiols in the presence of polyethylene glycol (PEG) to afford the
corresponding b-amino sulfides in high yields with good regioselectivity under mild and neutral conditions. The PEG can be recov-
ered and reused.
Ó 2006 Elsevier Ltd. All rights reserved.
The chemistry of aziridines continues to attract the
attention of the synthetic community. In fact, this inter-
thesis and organic reactions without the use of harmful
organic solvents are of great interest in organic synthe-
1
1
3
est is driven by the useful properties of aziridines centred
sis. Recently, attention has been drawn to the develop-
ment of environmentally benign solvents such as ionic
2
around their ring-opening transformations. The reac-
1
4
15
16
tivity of aziridines as carbon electrophiles makes them
versatile nitrogen containing building blocks for the syn-
liquids, water and polyethylene glycol. The value
of a new solvent medium primarily depends on its
environmental impact, the ease with which it can be
recycled, nonflammability and high polarity for solubili-
zation. Moreover, in performing the majority of organic
transformations, solvents play an important role in mix-
ing the ingredients to make the system homogeneous so
allowing molecular interactions to be more efficient.
Initially, our efforts directed towards the cleavage of
tosylaziridines in ethanol and ethylene glycol with
thiophenol. In this direction, we used N-substituted azir-
idines (Table 1, entry 3, 6, 7 and 16) for cleavage with
thiophenol in ethanol and ethylene glycol. The desired
products are not obtained after longer reaction times
and the starting materials were recovered.
3
thesis of biologically important compounds. The cleav-
age of tosylaziridines with thiols is interesting because
the resultant b-amino sulfides are important for the syn-
thesis of many biologically interesting molecules such as
4
5
6
amino acids, heterocycles and alkaloids. The simple
and most straightforward route to b-amino sulfides in-
volves the regioselective ring opening of tosylaziridines
7
with thiols using acid or base catalysts. Lewis acids
such as boron trifluoride etherate and zinc chloride as
well as Bronsted acids-like trifluoromethanesulfonic
7
,8
acid have been employed as acid catalysts. However,
many of these methods suffer from the fact that a Lewis
9
acid or strong base was necessary to effect the reaction.
Moreover, varied reaction conditions are needed for
various aziridines because of the different reactivity of
substrates and reagents, as well as the complexity of
Polyethylene glycol (PEG) a biologically acceptable
polymer used extensively in drug delivery and in biocon-
jugates as tool for diagnostics, has hitherto not been
widely used as a solvent medium but has been used as
1
0–12
the structure of aziridines.
Furthermore, these re-
agents cannot be recovered and recycled because they
decompose or are deactivated under quenching condi-
tions. The development of environmentally benign and
clean synthetic procedures is important in organic syn-
1
6,17
a support for various transformations.
More re-
cently, we demonstrated PEG as an efficient recyclable
1
8
reaction medium. With this background, we wish to
highlight our results on the application of PEG as a
recyclable reaction medium in the regioselective ring-
opening reaction of tosylaziridines with various thiols.
To the best of our knowledge, this is the first report
on the use of PEG as a reaction medium for the cleavage
of tosylaziridines with various thiols resulting in the
Keywords: PEG; Aziridines; Thiophenols; b-Amino sulfides.
*
Corresponding author. Tel.: +91 40 27193157; fax: +91 40
7193189; e-mail addresses: ahmedkamal@iict.res.in; ahmedkamal@
2
iictnet.org
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.086

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A. Kamal et al. / Tetrahedron Letters 47 (2006) 2261–2264
Table 1. PEG-mediated ring opening of tosylaziridines with thiophenols
a
Entry
Aziridine
Product
NHTs
Time (h)
Yield (%)
S-Ar
1
2
2a Ar = Ph
1.0
1.2
95
95
N-Ts
6 4
2b Ar = C H -p-Cl
N-Ts
NHTs
S-Ar
3
4
5
2c Ar = Ph
1.0
1.5
1.3
92
90
95
N-Ts
N-Ts
N-Ts
6 4
2d Ar = C H -p-Cl
6 4
2e Ar = C H -p-OMe
NHBOC
S-Ar
6
2f Ar = Ph
2.0
90
N-BOC
S-Ar
NHTs
R
N-Ts
7
8
2g Ar = Ph
1.5
1.5
85
88
R
R
R = H
R = H
N-Ts
N-Ts
N-Ts
N-Ts
N-Ts
6 4
2h Ar = C H -p-Cl
9
2i Ar = C
6
H
4
-p-OMe
1.5
2.0
1.3
1.3
85
85
90
85
R
R
R
R
R = H
R = H
R = Cl
R = Cl
10
11
12
2j Ar = 2-naphthyl
2k Ar = Ph
6 4
2l Ar = C H -p-Br

A. Kamal et al. / Tetrahedron Letters 47 (2006) 2261–2264
2263
Table 1 (continued)
a
Entry
Aziridine
Product
Time (h)
1.5
Yield (%)
N-Ts
N-Ts
N-Ts
13
14
15
6 4
2m Ar = C H -p-OMe
85
R
R = Cl
2n Ar = Ph
1.3
1.5
85
85
R
R
R = Me
R = Me
2o Ar = C
6
H
4
-p-OMe
S-Ar
NHTs
1
6
7
3p Ar = Ph
2.0
2.0
85
88
N-Ts
N-Ts
1
6 4
3q Ar = C H -p-Cl
S-Ar
NHTs
18
3r Ar = C
6
H
4
-p-Cl
2.0
85
N-Ts
a
Isolated yields.
formation of corresponding b-amino sulfides. Accord-
ingly, treatment of tosylaziridine with thiophenol in
the presence of PEG 400 (Table 1, entry 1) at room tem-
perature for 1 h, resulted in the generation of b-amino
sulfide in 95% yield (Scheme 1).
reaction proceeds efficiently at room temperature with-
out the use of any further acid or base catalyst and goes
1
9
to completion in a short time (Table 1). Smaller quan-
tities of the other regioisomer were obtained for unsym-
metrical aziridines (5–15%). 2-Aryl substituted
aziridines were obtained with the opposite regioselectiv-
ity in comparison to 2-alkyl aziridines. In the case of
cycloalkyl aziridines, the stereochemistry of the ring
cleaved product 2c was found to be trans from the coup-
In a similar fashion, other tosylaziridines reacted
smoothly with various thiols to afford the corresponding
b-amino sulfides in high yields (Schemes 1 and 2). The
ling constant values of the ring hydrogen at d: 2.89
1
(
ddd, 1H, J = 4.1, 9.4, 9.8 Hz, CHS) in the H NMR
NHX
spectrum and the peak at d: 2.98 (ddd, 1H, J = 4.0,
9.2, 9.6 Hz) for CHN showed a similar splitting. Bicyclic
N-tosylaziridines cleaved smoothly with thiols to afford
the corresponding b-amino sulfides.
PEG, rt
N-X
+
R'-SH
(
)n
( )n
SR'
X = Tosyl, BOC
n = 1, 2
1
2
The activity of polyethylene glycol (PEG) for the cleav-
age of tosylaziridines was established by the fact that
there was no reaction in the absence of PEG. The role
R' = C H ,
p-Cl-C H , p-OMe-C H
6 4 6 4
6
5
Scheme 1.
NHTs
SR'
SR'
PEG, rt
N-Ts
+
R'-SH
+
NHTs
R
R
p
R
2
3
1
R = alkyl, aryl
R' = C H , -Cl-C H ,
p
-Br-C H , p-OMe-C H 2-naphthyl
6 4 6 4,
6
5
6
4
Scheme 2.

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A. Kamal et al. / Tetrahedron Letters 47 (2006) 2261–2264
of PEG appears to be not only to activate the tosylazir-
idine by hydrogen bonding but also to favour a-attack
at the tosylaziridine resulting in high regioselectivity.
Fujiwara, Y.; Ihara, H.; Uneyama, K. J. Org. Chem. 1999,
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611–1613; (c) Lee, W. Y.; Salvador, J. M.; Bodige, K.
In summary, PEG has been found to be a useful, cost-
effective, environmental friendly and efficient alternative
for the regioselective ring opening reactions of tosylazir-
idines with thiols under mild conditions. Further appli-
cations of PEG as a recyclable reaction medium for
various organic transformations are under investigation
in our laboratory.
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Acknowledgements
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2
473–2482; (b) Lucet, D.; Gallo, T. L.; Mioskowski, C.
The authors D.R.S.R. and Rajendar are grateful to
CSIR, New Delhi, for the award of research fellowships.
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19. General procedure: To a stirred suspension of an aziridine
(1 mmol) in PEG 400 (2 g), the thiol (1 mmol) was added
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tored by TLC). The reaction mixture was extracted with
dry ether, the solvent was removed under reduced pressure
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with negligible loss of its activity. Spectral data for the
1
compound 2c: H NMR (200 MHz, CDCl
) d: 1.22–1.45
3
(m, 4H), 1.50–1.74 (m, 2H), 1.94–2.05 (m, 1H), 2.23–2.32
(m, 1H), 2.44 (s, 3H), 2.89 (ddd, 1H, J = 4.1, 9.4, 9.8 Hz),
2.98 (ddd, 1H, J = 4.0, 9.2, 9.6 Hz), 5.10 (br s, NH, 1H),
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5256.
8
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+
Æ
m/z = 361 [M ].