Ceric ammonium nitrate (CAN) catalyzed ring cleavage of N-tosyl aziridines: A potential tool for solution phase library generation

Article abstract of DOI:10.1016/S0040-4039(02)01718-5

A range of N-tosylaziridines is cleaved with NaN₃, H₂O, MeOH to synthesize vicinal azidoamines, aminols and amino ethers in good to excellent yields catalyzed by ceric ammonium nitrate and used in solution phase library synthesis.

Full text of DOI:10.1016/S0040-4039(02)01718-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7361–7363
Ceric ammonium nitrate (CAN) catalyzed ring cleavage of
N-tosyl aziridines: a potential tool for solution phase library
generation†
S. Chandrasekhar,* Ch. Narsihmulu and S. Shameem Sultana
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 5 June 2002; revised 5 August 2002; accepted 16 August 2002
Abstract—A range of N-tosylaziridines is cleaved with NaN3, H2O, MeOH to synthesize vicinal azidoamines, aminols and amino
ethers in good to excellent yields catalyzed by ceric ammonium nitrate and used in solution phase library synthesis. © 2002
Elsevier Science Ltd. All rights reserved.
Vicinal diamines and aminols are medicinally important
compounds.1 These compounds are usually prepared by
ring opening of epoxides or/and N-substituted aziridi-
nes with appropriate nucleophiles. The nucleophiles
include halogen,2 nitrogen,3 carbon4 and hydrogen5
which permit the generation of diverse combinatorial
libraries.
The screening of several reagents and catalysts allowed
us to shortlist ceric ammonium nitrate (CAN) as a
versatile catalyst to effect this transformation. The
results pertaining to this study are presented herein
(Scheme 1). This protocol allowed us to synthesize a
library of 24 compounds.
Initially, our efforts began with cyclohexyl-N-tosyl-
aziridine (Table 1, entry 1) which was treated with 10
mol% CAN in acetonitrile–water (9:1) and after 8 h,
clean formation of the aminol derivative 1a was
obtained in 95% yield after a simple workup. To
explore the usefulness of this transformation, the same
aziridine was treated with 1.5 equiv. of NaN3 in aceto-
nitrile/water (9:1) mixture for 3 h (at 60°C, as the
reaction was sluggish at rt) to yield the azidoamine 1c
in 95% yield. The nucleophilic opening of the substrate
with NaN3 did proceed in the absence of CAN, with
about 60% conversion in 36 h.
The ring opening of activated aziridines with oxygen
nucleophiles is reported with mineral acids6 and
7
recently Lewis acids, BF3·OEt2 and Sn(OTf)2 have
been used with water and alcohols under very mild
conditions. Surprisingly, however, other Lewis acids
such as Cu(OTf)2, CuCl2, SnCl2, AlCl3, FeCl3, LiClO4,
CoCl2 and ZnCl2 did not perform this transformation
efficiently.7 As part of a long term programme address-
ing the development of new methods8 for the synthesis
of bioactive amines9 and aminols, we desired a general
method for the opening of N-tosylaziridines with nucleo-
philes viz, OH, OR and N3.
Encouraged by this finding, a phenyl-N-tosylaziridine
derivative (entry 4) was treated with CAN in acetoni-
trile/water (9:1) both in the absence and presence of
NaN3 to yield 2-phenyl-2-hydroxy-N-tosylamino eth-
ane 4a and 2-phenyl-2-azido-N-tosylamino ethane 4c in
92% and 93% yields, respectively. As expected in
methanol as a solvent, OCH3 added as the nucleophile
in both the cases studied (1b and 4b). To prove the
usefulness of this methodology, a series of eight aziridi-
nes was prepared and subjected to the three nucleo-
philes namely H2O, MeOH and NaN3 in a com-
binatorial fashion10 using a multiple synthesizer to
yield 24 compounds in acceptable purities and yields in
two operations following a simple workup and filtra-
Scheme 1.
Keywords: N-substituted aziridines; ceric ammonium nitrate; cleav-
age; NaN3; H2O; MeOH; vicinal azidoamines; solution phase library.
* Corresponding author. Tel.: +91 40 7193434; fax: +91 40 7160512;
e-mail: srivaric@iict.ap.nic.in
† IICT communication No. 080202.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01718-5

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S. Chandrasekhar et al. / Tetrahedron Letters 43 (2002) 7361–7363
Table 1. Ring opening of N-tosylaziridines
tion. With reference to regiochemistry of the ring open-
ing, as expected, it was observed that in the case of
benzylic aziridines, electronic factors controlled the ring
opening whereas in the case of unsymmetrical terminal
aziridines, steric factors controlled the regioselectivity.
Some of the functionalities studied, which were stable
to CAN, included the aryl bromide group (entry 6), the
aromatic methoxy group (entry 5), and the ester func-
tionality (entry 8). The vicinal N-tosylaminols (1a–8a),
methoxy-N-tosylamines (1b–8b) and azido-N-tosylazi-
doamines (1c–8c) synthesized are being explored as
building blocks for new chemical entities.
In conclusion, a mild protocol has been developed for
the ring opening of N-tosylaziridines with H2O, MeOH
and NaN3 as nucleophiles which should find applicabil-
ity in medicinal chemistry and complex natural product
synthesis.11,12

S. Chandrasekhar et al. / Tetrahedron Letters 43 (2002) 7361–7363
7363
Acknowledgements
10. The tabletop organic synthesizer ‘Carousel’ stirring hot
plate was used. While synthesizing the compounds on the
organic synthesizer, the initial reactions were kept at
room temperature for 8 h after which the completed
reactions with MeOH and H2O were taken out of reac-
tion block. The remaining tubes were heated at 60°C for
2 h to allow the NaN3 reactions to be completed.
11. Representative procedures: Method A: To N-tosyl-
aziridine (2 mmol) in 5 mL of acetonitrile/water (9:1) was
added CAN (0.2 mmol) and the mixture left stirring at
room temperature (1–6 samples placed in a multiple
synthesizer). After 8 h the reaction mixture was diluted
with water and extracted with ether (3×10 mL). The
combined organic layers were dried over Na2SO4, con-
centrated in vacuo and purified by column
chromatography.
Two of us, C.N. and S.S.S., are thankful to CSIR, New
Delhi for financial assistance.
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Method B: To N-tosylaziridine (2 mmol) in 5 mL of
methanol was added CAN (0.2 mmol) and the mixture
left stirring at room temperature (1–8 samples placed in a
multiple synthesizer). After 8 h the solvent was removed,
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Method C: To N-tosylaziridine (2 mmol) in 5 mL of
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