Short and efficient synthesis of optically active N-tosyl aziridines from 2-amino alcohols

Article abstract of DOI:10.3390/71200902

Two alternative and complementary one-pot procedures for the direct transformation of 2-amino alcohols to N-tosyl aziridines are presented. The unsubstituted parent compound and its less hindered homologues can be obtained in high yields by tosylation and

Full text of DOI:10.3390/71200902

Molecules 2002, 7, 902-906
molecules
ISSN 1420-3049
http://www.mdpi.org
Short and Efficient Synthesis of Optically Active N-Tosyl
Aziridines from 2-Amino Alcohols
*
Lothar W. Bieber and Maria C. F. de Araújo
Departamento de Química Fundamental, Universidade Federal de Pernambuco, 50607-901 Recife –
PE, Brazil
*Author to whom correspondence should be addressed; e-mail: bieberlothar@hotmail.com
Received: 3 November 2002; in revised form: 2 December 2002 / Accepted 2 December 2002 /
Published 31 December 2002
Abstract: Two alternative and complementary one-pot procedures for the direct
transformation of 2-amino alcohols to N-tosyl aziridines are presented. The unsubstituted
parent compound and its less hindered homologues can be obtained in high yields by
tosylation and in situ cyclisation effected by potassium hydroxide in
water/dichloromethane. Higher substituted amino alcohols give better yields using
potassium carbonate in acetonitrile. Both procedures use simple inorganic bases and
produce only inorganic salts as byproducts.
Keywords: Amino alcohols, bis-tosylation, inorganic bases, 1,3-elimination, aqueous
solvent.
Introduction
Aziridines are interesting synthetic building blocks for the construction of complex nitrogen
containing compounds. When activated by a N-tosyl group, they are especially reactive towards
nucleophilic ring opening and provide an easy access to a wide variety of alkaloid structures [1].
Although several methods have been reported for the direct asymmetric transfer of N-tosyl nitrene to

Molecules 2002, 7
903
olefinic double bonds in recent years [2], the most obvious precursors for chiral N-tosyl aziridines 1
are 2-amino alcohols 3 derived from natural or unnatural amino acids 4. Initially, compounds of type 1
have been prepared in moderate yields via the unstable bis-tosylates 2 using traditional acylation and
ring closure procedures [1b,3]. Alternatively, N-tosylated amino acids 5 have been reduced to the
alcohols 6, submitted to a second tosylation and cyclised in situ to 1 (Scheme 1) [4].
Scheme 1: Synthesis of N-tosylaziridines
Method A: TsCl, K2CO3, MeCN, 6 h
Method B: TsCl, KOH, H2O / CH2Cl2, 30 min
CH2OH
CH2OTs
KOH / MeOH
TsCl / pyridine
NTs
R
NH2
R
R
NHTs
1
2
3
TsCl pyridine
LiAlH4 THF
COOH
CH2OH
COOH
LiAlH4 / THF
TsCl / EtNiPr2
R
NH2
R
NHTs
R
NHTs
5
6
4
Although the latter procedure is high yielding, it requires several steps and anhydrous reaction
conditions. The first inconvenient has been avoided in two procedures previously described for special
intermediates in alkaloid syntheses: (S)-leucinol (3, R = CH2iPr) has been transformed in a one-pot
procedure to the corresponding N-tosylaziridine 1 using excess of tosyl chloride and triethylamine and
catalytic amounts of 4-dimethylaminopyridine in dichloromethane [5], similarly, the chiral key
intermediate 1 (R = nPr) of our Pumiliotoxin C synthesis has been obtained directly from (S)-
norvalinol with sodium hydride as base in anhydrous THF [6]. However, the experimental risks due to
the use and destruction of large amounts of hydride and the need for anhydrous reagents and solvents,
represented serious limitations for a general application, especially under tropical conditions of
extreme humidity, and prompted us to look for less hazardous solvent/base combinations.
Results and Discussion
In previous work, anhydrous potassium carbonate in aprotic, but undried commercial solvents has
been useful for the alkylation of 1,3-dicarbonyl compounds [7] and a similar procedure seemed
promising for the direct acylation of 3 and subsequent ring closure to 1. Indeed, first experiments using
this base in undried DMF, DMSO or HMPA as solvent at room temperature produced 1 in moderate

Molecules 2002, 7
904
yields, but the crude product contained considerable amounts of polymeric material and required
chromatographic purification. Use of a weaker base like potassium bicarbonate or fluoride stopped the
reaction partially at the level of compounds 2 and did not avoid polymerization. Finally, when K CO3
2
was used in commercial undried acetonitrile, a smooth and clean reaction was accomplished in 6 h at
room temperature and high yields of several substituted (S)-aziridines 1 were obtained after separation
of insoluble salts and evaporation of the solvent (Table 1, entries 4-9, method A).
Table 1. Direct synthesis of (S)-N-tosyl aziridines 1 from (S)-amino alcohols 2.
Method A Method B
Entry R =
Yield %
46
Yield %
74
1
2
3
4
5
6
7
8
9
H
CH3
53
78
C2H5
62
86
(CH3)2CH
CH3 CH2CH2
(CH3)2CHCH2
C6H5 CH2
CH3SCH2CH2
4-HO-C6H4CH2
75
70
82
73
76
52
92
64
85
67
a
87
58
a
Bis-tosylate was obtained using 3.2 (Method
A) and 3.5 (Method B) eq. of tosyl chloride,
respectively.
However, when the same method was applied to unsubstituted aminoethanol 3 (R = H, entry 1) and
the lower amino alcohols (entries 2 and 3), the yields and purities of the compounds 1 obtained were
unsatisfactory. As unsubstituted tosyl aziridine has been obtained before in excellent yield by
cyclisation of bis-tosylate 2 (R = H) using aqueous potassium hydroxide [8], we tried to combine
tosylation and 1,3-elimination in the same solvent/base system. In fact, when tosyl chloride was added
to a vigorously stirred mixture of 2-aminoethanol, concentrated aqueous potassium hydroxide and
methylene chloride, good yields of the desired tosyl aziridine 1 (R = H) were obtained in a few minutes
(Table 1, entry 1, method B). The same procedure proved to be superior or equivalent to method A in
the case of small and medium size substituents (entries 2-5), but was less efficient for the higher
substituted amino alcohols, probably because in these cases one of the tosylation steps is complicated
by steric hindrance. On the other hand, in method A the long reaction time leads to partial
polymerization of aziridines bearing smaller substituents.

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Conclusions
In conclusion, both methods described herein are short, simple and safe experimental procedures;
they are complementary alternatives depending on the steric hindrance of the starting amino alcohol.
Both methods make use of inexpensive and easily neutralized inorganic bases and the organic solvents
used can be recovered by distillation. The use of moisture sensitive and hazardous reagents and
formation of organic waste is avoided. Combined with known methods of sodium borohydride
reduction of amino acids 4 [9] they allow one to carry out the whole sequence from 4 to 1 (Scheme 1)
using inexpensive reagents and environmentally friendly solvents.
Acknowledgements
This work was supported by grants from CNPq (Brasilia). We thank M. Ricardo O. da Silva for
GC-MS analyses.
Experimental
General
All reagents and solvents from commercial suppliers were used without further purification. All
products obtained had physical and spectroscopic properties identical to those reported in the literature
[3,4,6].
Typical Synthetic Procedures
Method A: Tosyl chloride (2.2 mmol) was added portionwise at r.t. to a stirred mixture of 3 (1.0
mmol), K2CO3 (4.0 mmol) and acetonitrile (2.0 mL). After 6 h, toluene (5 mL) was added, the solid
was filtered off and the solvents evaporated.
Method B: Tosyl chloride (2.5 mmol) was added portionwise at r.t. under vigorous stirring to a mixture
of KOH (2.0 g), 3 (1.0 mmol), water (2.0 mL) and CH Cl2 (2.0 mL). After 30 min, ice and water were
2
added, the organic layer was separated, washed with water, dried over MgSO4 and evaporated.
The crude products were purified by crystallization, short-path distillation or column chromatography.
The optical purities of all products were proven to be identical with those of the starting materials. The
pure aziridines polymerize at r.t. within a few days, but can be stored at –30º for months.

Molecules 2002, 7
906
References
1. (a) Tanner, D. Angew. Chem. Int. Ed. Engl. 1994, 33, 599-619; (b) Osborn, H.M.I.; Sweeney, J.
Tetrahedron Asymmetry 1997, 8, 1693-1715.
2. (a) Halfen, J.A.; Hallman, J.K.; Schultz, J.A.; Emerson, J.P. Organometallics 1999, 18, 5435-5437;
(b) Albone, D.P.; Aujla, P.S.; Taylor, P.C.; Challenger, S.; Derrick, A.M. J. Org. Chem. 1998, 63,
9569-9571.
3. Daub, G.W.; Heerding, D.A.; Overman, L.E. Tetrahedron 1988, 44, 3919-3930.
4. Berry, M.B.; Craig, D. Synlett 1992, 41-45.
5. (a) Craven, A.P.; Dyke, H.J.; Thomas, E.J. Tetrahedron 1989, 45, 2417-2429; (b) Wang, J.Q.;
Zhong, M.; Lin, G.Q. Chin. J. Chem.1998, 16, 65-77.
6. Oppolzer, W.; Flaskamp, E.; Bieber, L.W. Helv. Chim. Acta 2001, 84, 141-145.
7. Araújo, A.C.V.; Almeida, F.V., Bieber, L.W. Química Nova 1996,19, 79-81.
8. Martin, A.E.; Ford, T.M.; Bulkowski, J.E. J. Org. Chem. 1982,47, 412-415.
9. (a) McKennon, M.J.; Meyers, A.I.; Drauz, K.; Schwarm, M. J. Org. Chem. 1993, 58, 3568-3571;
(b) Abiko, A.; Masamune, S. Tetrahedron Lett. 1992, 33, 5517.
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