Efficient synthesis of chiral 1,1′-sulfonyl bisaziridines

Article abstract of DOI:10.1080/00397910600639802

An efficient three-step synthesis of chiral 1,1′-(sulfonyl) bisaziridines is described. Preparation of these compounds was carried out easily starting from N,N′-sulfonyl bis-(α-L-aminoester) to afford the title compounds in very good yields. These 1,1′-(s

Full text of DOI:10.1080/00397910600639802

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Efficient Synthesis of Chiral 1,1′‐Sulfonyl
Bisaziridines
Nawel Khettache a , Amel Bendjeddou a , Malika Berredjem a , Zine Regainia
a , Veronique Montero b , Chantal Menut b , Nour‐Eddine Aouf a & Jean‐Yves
Winum b
a Laboratoire de Chimie Bioorganique , Université d'Annaba , Annaba,
Algéria
b Laboratoire de Chimie Biomoléculaire , Université Montpellier II ,
Montpellier Cedex, France
Published online: 22 Sep 2006.
To cite this article: Nawel Khettache , Amel Bendjeddou , Malika Berredjem , Zine Regainia , Veronique
Montero , Chantal Menut , Nour‐Eddine Aouf & Jean‐Yves Winum (2006) Efficient Synthesis of Chiral
1,1′‐Sulfonyl Bisaziridines, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 36:16, 2299-2305, DOI: 10.1080/00397910600639802
To link to this article: http://dx.doi.org/10.1080/00397910600639802
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Synthetic Communicationsw, 36: 2299–2305, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600639802
Efficient Synthesis of Chiral 1,10-Sulfonyl
Bisaziridines
Nawel Khettache, Amel Bendjeddou, Malika Berredjem,
and Zine Regainia
´
Laboratoire de Chimie Bioorganique, Universite d’Annaba, Annaba,
´
Algeria
Veronique Montero and Chantal Menut
´ ´
Laboratoire de Chimie Biomoleculaire, Universite Montpellier II,
Montpellier Cedex, France
Nour-Eddine Aouf
Laboratoire de Chimie Bioorganique, Universite d’Annaba, Annaba,
´
Algeria
´
Jean-Yves Winum
´ ´
Laboratoire de Chimie Biomoleculaire, Universite Montpellier II,
Montpellier Cedex, France
Abstract: An efficient three-step synthesis of chiral 1,10-(sulfonyl)bisaziridines is
described. Preparation of these compounds was carried out easily starting from
N,N0-sulfonyl bis-(a-L-aminoester) to afford the title compounds in very good
yields. These 1,10-(sulfonyl)bisaziridines can constitute interesting synthetic building
blocks.
Keywords: Sulfonylbisaziridine, sulfamide, aziridine, heterocycle
Received in the U.K. June 27, 2005
Address correspondence to Jean-Yves Winum, Laboratoire de Chimie Biomolecu-
´
´
laire, UMR 5032, Universite Montpellier II, ENSCM, 8 Rue de l’Ecole Normale,
34296 Montpellier Cedex, France. E-mail: yves.winum@univ-montp2.fr
2299

2300
N. Khettache et al.
INTRODUCTION
Aziridines constitute an important class of heterocyclic compounds, which
have found use in organic and medicinal chemistry.[1] They form a part of
several natural products, and they are useful intermediates for the preparation
of interesting biological molecules such as amino acids,[2] heterocycles,[3] and
alkaloids.[4] Moreover, aziridines have important synthetic value, as they are
able to react with various nucleophiles and to undergo regioselective ring-
opening reactions.[5]
Among all the aziridine derivatives described in literature, 1,10-sulfonyl-
bisaziridine constitutes an original intermediate with potential applications in
medicinal chemistry. Moreover, it can be considered as a sulfonyl equivalent
of 1,10-carbonylbisaziridine and also of TEPA (N,N0,N00-triethylenephosphor-
amide) compounds, such as thioTEPA (N,N0,N00-triethylenethiophosphora-
mide) which is well known for its anticancer properties.[6]
Despite their potential as synthetic intermediates for the preparation of
compounds with potential biological interest, chiral 1,10-sulfonylbisaziridines
have received very little attention in the literature. Up to now, very few
examples of such compounds have been reported. Only the synthesis of the
nonsubstituted 1,10-sulfonylbisaziridine has been previously described using
direct coupling of aziridine with sulfuryl chloride.[7,8]
Herein, we report a simple and efficient method for the synthesis
of chiral 1,10-sulfonylbisaziridines from the ring-closing reaction of the
bis-(chloroethylamino) precursor.
CHEMISTRY
Chiral 1,10-sulfonylbisaziridines 4a–c have been obtained in three steps
starting from N,N0-sulfonyl bis-(a-L-aminoester) 1a–c prepared as previously
described.[9] In the first step (Scheme 1), the reduction of 1a–c with LiAlH4 in
anhydrous THF provided N,N0-bis (1-alkyl-2-hydroxyethyl) sulfamides 2a–c
in 80% yield. Chlorination of 2a–c using SO2Cl2/TEA at 2788C furnished
the corresponding N,N0-bis (1-alkyl-2-chloroethyl) sulfamides 3a–c in high
yields. At this stage, the aziridine rings were generated by a cyclization
reaction using K2CO3 in acetonitrile (Scheme 1) to yield substituted 1,10-
sulfonylbisaziridines 4a–c.
The structures of all compounds were unambiguously confirmed by the
usual spectroscopic and spectrometric analysis. In compound 4c, we notice

1,10-Sulfonyl Bisaziridines
2301
Scheme 1. Reagents and conditions: (i) LiAlH4, THF, 08C 1 h, and reflux 3 h (80%);
(ii) SO2Cl2, Et3N, CH2Cl2, 2788C 3 h, and rt 10 h (70%), (iii) K2CO3, CH3CN, rt 5 h
(85%).
the nonequivalence of the methylene protons in the isobutyl group that appear
in the NMR spectrum as two multiplets at d 1.25 and d 1.52. Similarly, the two
protons of the aziridine rings methylene group were nonequivalent. For the
three final derivatives 4a–c,the different NMR spectra showed a pair of
doublets, due to the adjacent methine proton at C-2, at d 2.15 and d 2.62
(Dd ꢀ 0.50 ppm) with coupling constants J ¼ 4.60 Hz and J ¼ 6.90 Hz in
the cyclic system. Moreover, all the compounds exhibited characteristic
absorption bands (SO2) in the infrared spectrum at 1110–1170 cm21 and
1340–1390 cm21
.
CONCLUSION
An expedient route has been developed for the preparation of bis-aziridinyl-
sulfones (4a–c). The synthesis has been performed easily starting from
N,N0-sulfonyl bis-L-amino esters. The strategy we describe is highly
flexible and applicable to the synthesis of an array of scaffolds with
different modifications on the side chain. This work now provides reliable
access to this class of derivatives and opens the way to further applications.
Work along this line is currently in progress.
EXPERIMENTAL
General
Melting points were determined in open capillary tubes on a Bu¨chi apparatus
and are uncorrected. IR spectra were recorded on a Perkin-Elmer spec-
trometer. Proton nuclear magnetic resonance was determined with an AC
250-MHz Bruker spectrometer. Chemical shifts are reported in d units

2302
N. Khettache et al.
(ppm). All coupling constants J are reported in Hertz. Multiplicity is indi-
cated as s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet) and
combination of these signals. Electron ionization mass spectra (30 eV) were
recorded in positive or negative mode on a Water MicroMass ZQ. Optical
rotations were measured in a 1-cm cell on a Perkin-Elmer polarimeter. All
reactions were monitored by TLC on silica Merck h60 F254 precoated
aluminium plates and were developed by spraying with ninhydrin solution.
Column chromatographies were performed on Merck silica gel (230–400
mesh).
General Procedure for the Reduction of N,N0-sulfonyl-bis-L-
aminoesters
One equiv. of bis-L-aminoestersulfone 1 in anhydrous THF was added
dropwise to 3.5 eq. of lithium aluminium hydride in the same solvent at
08C, and the medium was refluxed with stirring for 3.5 h. The reaction was
cooled in an ice bath, and the excess of lithium aluminium hydride was
neutralized by addition of THF-H2O (4/1). The resulting solution was stirred
for 1 h and then filtered through Celitew. The solvent was removed under
reduced pressure, and the solution was extracted with ethyl acetate. The organic
layer was dried over anhydrous sodium sulfate and concentrated under vacuum.
Data
S,S-N,N0-bis (1-Benzyl-2-hydroxyethyl) sulfamide (2a): White solid; yield
80%, mp 97–988C; TLC: Rf ¼ 0.70 (CH2Cl2-MeOH, 9 : 1); [a]D ¼ þ36.268
(c ¼ 0.10 MeOH); IR (KBr, n cm21) 3668 (OH), 3328, 3258 (NH), 1330
and 1134 (SO2). 1H NMR (CDCl3, 250 MHz) d: 2.75–3.0 (m, 8H,
CH2Ph þ CH2OH), 3.30–3.75 (m, 6H, C H þ OH þ NH), 7.30 (m, 10H, H
*
arom); 13C NMR (CDCl3, 250 MHz) d: 38.16, 46.74, 55.20, 127.18, 128.65,
129.40, 136.43; MS ESIþ 30 eV m/z: 387 [M þ Na]þ.
S,S-N,N0-bis (1-Isopropyl-2-hydroxyethyl) sulfamide (2b): White solid;
yield 80%; mp 110–1128C; TLC: Rf ¼ 0.54 (CH2Cl2-MeOH, 9 : 1),
[a]D ¼ 26.268 (c ¼ 0.74 MeOH); IR (KBr, n cm21) 3471 (OH), 3282,
1
3220 (NH), 1326 and 1118 (SO2); H NMR (CDCl3, 250 MHz) d: 0.85
(2 ꢀ d, J ¼ 6.4 Hz, 12H, 4CH3), 1.82 (m, 2H, 2CH), 3.0 (m, 2H, 2C H),
*
3.40 (m, 4H, 2CH2), 4.72 (m, 2H, 2OH), 6.3 (d, J ¼ 8.2 Hz, 2H, 2NH); 13C
NMR (CDCl3, 250 MHz) d: 16.70, 17.80, 27.45, 40.40, 52.60; MS ESI2 20
eV m/z: 267.05 [M-H]2; ESIþ 30 eV m/z: 291.16 [M þ Na]þ.
S,S-N,N0-bis [1-Isobutyl-2-hydroxyethyl) sulfamide (2c): White solid;
yield 83%; mp 100–1028C; TLC: Rf ¼ 0.37 (CH2Cl2-MeOH, 9 : 1);
[a]D ¼ þ21.268 (c ¼ 0.10 MeOH); IR (KBr, n cm21) 3668 (OH), 3328,

1,10-Sulfonyl Bisaziridines
2303
1
3258 (NH), 1330, 1134 (SO2); H NMR (CDCl3, 250 MHz) d: 0.85 (2 ꢀ d,
J ¼ 6.0 Hz, 12H, 4CH3), 1.25 (m, 4H, 2CH2 iBu), 1.70 (m, 2H, 2CH iBu),
3.30–3.50 (m, 4H, 2C H þ 2NH), 3.65 (s, 2H, 2 OH), 3.75 (m, 4H,
*
2CH2O); 13C NMR (CDCl3, 250 MHz) d: 22.38, 22.69, 24.53, 41.07, 54.64,
64.90; MS ESIþ 30 eV m/z: 319.34 [M þ Na]þ, 297.34 [M þ H]þ; ESI2 20
eV m/z: 295.17 [M-H]2.
General Procedure for Chlorination
The compound N,N -bis (1-alkyl-2-hydroxyethyl) sulfamide 2 was dissolved
in dry dichloromethane under an argon atmosphere. Triethylamine (2.5 eq.)
was added to the solution at 2788C. Sulfuryl chloride (0.5 eq.) was added
dropwise to the solution, and the reaction mixture was kept under constant
stirring at 2788C for 3 h. The reaction mixture was allowed to warm to
room temperature for 10 h. The mixture was washed with HCl 1 N and
water. The organic layer was dried over anhydrous sodium sulfate and
removed under reduced pressure. The residue was purified on a silica-gel
column (CH2Cl2) to afford the expected product 3 in good yield.
Data
S,S-N,N0-bis (1-Benzyl-2-chloroethyl) sulfamide (3a): White oil; yield 82%,
Rf ¼0.50 (CH2Cl2); [a]D ¼ 22.728 (c ¼ 0.11, CHCl3); IR (CCl4, n cm21):
1
3228 (NH), 1292 and 1149 (SO2); H NMR (CDCl3, 250 MHz): d 2.8–3.15
(m, 4H, CH2-Ph), 3.30–3.80 (m, 2H,
CH), 4.20 (2 ꢀ d, J ¼ 2.8 Hz,
*
J ¼ 2.5 Hz, 1H), 5.50 (m, 2H, 2NH), 7.30 (m, 10H, H arom); 13C NMR
(CDCl3, 250 MHz) d: 39.16, 46.74, 53.20, 127.24, 128.75, 129.65, 136.45;
MS ESIþ 30 eV m/z: 422.92 [M þ Na]þ; ESI2 20 eV 399 [M2H]2.
S,S-N,N0-bis (1-Isopropyl-2-chloroethyl) sulfamide (3b): White solid; yield
70%; Rf ¼ 0.60 (CH2Cl2); mp 80–828C; [a]D ¼ þ598 (c ¼ 0.38, CHCl3); IR
1
(KBr, n cm21): 3298 (NH), 1326 and 1137 (SO2); H NMR (CDCl3, 250
MHz) d: 0.96 (2 ꢀ d, J ¼ 6.9 Hz, 12H, 4CH3), 2.00 (m, 2H, 2CH iPr), 3.42
(m, 2H, 2C H), 3.80 (m, 4H, 2CH2Cl), 4.50 (d, J ¼ 9.0 Hz, 2H, 2NH);
*
13C NMR (CDCl3) d: 17.70, 18.8, 31.5, 48.40, 54.80; MS ESIþ 30 eV m/z:
328.88 [M þ Na]þ, ESI2 20 eV m/z: 303.99 [M2H]2.
S,S-N,N0-bis (1-Isobutyl-2-chloroethyl) sulfamide (3c): Yellow oil; yield
80%, Rf ¼ 0.62 (CH2Cl2); [a]D ¼ 2298 (c ¼ 0.01, CH2Cl3); IR (CCl4, n
1
cm21): 3289 (NH), 1322 and 1126 (SO2); H NMR (CDCl3, 250 MHz) d:
0.98 (2 ꢀ d, J ¼ 6.0 Hz, 12H, 4CH3), 1.50 (m, 4H, 2CH2 iBu), 1.70
(m, 2H, 2CH iBu), 3.65 (dd, 2H, J ¼ 2.6, 3.6 Hz, 2CH), 3.70 (m, 2H,
2C H), 3.90 (dd, 2H, J ¼ 3.6, 4.10 Hz, 2CH), 4.42 (s, 1H, NH); 13C NMR
*

2304
N. Khettache et al.
(CDCl3, 250 MHz) d: 21.61, 21.88, 23.40, 40.46, 47.38, 52.18. MS ESIþ 30
eV m/z: 333.34 [M þ H]þ, ESIþ 20 eV m/z: 331.10 [M2H]2.
Typical Experimental Procedure for the Synthesis of 4a–c
A solution of 3 (0.10 g, 0.2 mmol) and K2CO3 (0.05 g, 0.3 mmol) in CH3CN
(20 ml) was stirred at room temperature for 5 h. The reaction was monitored
by TLC. Then the reaction mixture was filtered and concentrated under
vacuum. The residue was purified on a silica-gel column using chloroform
as the eluent.
Data
S,S-N,N0-bis(2-Benzylaziridin-1-yl) sulfone (4a): Yellow oil yield 90%;
Rf ¼ 0.60 (CH2Cl2); [a]D ¼ 2128 (c ¼ 0.01, CH3OH); IR (CCl4, n cm21):
1
3289 (NH), 1322 and 1126 (SO2); H NMR (CDCl3, 250 MHz) d: 2.17
(d, J ¼ 4.4 Hz, 2H, 2C3H), 2.71 (m, 2H, 2C3H), 2.76–3.12 (m, 6H, 2
CH2Ph þ 2C H), 7.33 (m, 10H, H arom); 13C NMR (CDCl3, 250 MHz)
*
d: 39.60, 41.20, 43.40, 126.98, 128.64, 129.25, 136.93; MS ESIþ 30 eV m/z:
351.06 [MþNa]þ.
S,S-N,N’-bis(2-Isopropylaziridin-1-yl) sulfone (4b): White solid; yield 85%;
Rf ¼ 0.75 (CH2Cl2); mp 60–618C; [a]D ¼ þ82.908 (c ¼ 0.38, CHCl3); IR
1
(KBr n cm21): 1312 and 1120 (SO2); H NMR (CDCl3, 250 MHz) d: 1.10
(d, 12H, J ¼ 6.70 Hz, 4CH3), 1.54 (m, 2H, 2CH), 2.24 (m, 2H, 2C3H), 2.62
(m, 4H, 2C3H þ 2C H). 13C NMR (CDCl3, 250 MHz) d: 17.80, 18.80,
*
33.54, 40.20, 41.50. MS (ESIþ, 30 eV): 255.20 [MþNa]þ.
N,N0-bis (2-Isobutylaziridin-1-yl) sulfone (4c): Yellow oil; yield 90%; Rf
¼0.75 (CH2Cl2); [a]D ¼ 264.948 (c ¼ 0.97, CH2Cl2); IR (CCl4, n cm21):
1
1332 and 1144 (SO2); H NMR (CDCl3, 250 MHz) d: 0.8 (2 ꢀ d, J ¼ 2.0,
3.30 Hz, 4CH3), 1.30 (m, 2H, 2CH iBu), 1.55 (m, 2H, 2CH), 1.84 (m, 2H,
2CH), 2.15 (d, J ¼ 4.60 Hz, 2H, 2C3H), 2.62 (d, J ¼ 6.90 Hz, 2H, 2C3H),
2.78 (m, 2H, 2C H); 13C NMR (CDCl3, 250 MHz) d 22.05, 22.77,
*
26.65, 34.57, 39.34, 40.32. MS ESIþ 30 eV m/z: 283.28 [MþNa]þ, 261.29
[MþH]þ.
ACKNOWLEDGMENTS
` ´
Financial support of this work by the Ministere Algerien de l’Enseignement et
de la Recherche Scientifique (Fond National de la Recherche FNR2000,
´ ´
Algeria) and Agence Nationale pour la Recherche sur la Sante (ANDRS,
project no. 05/05/00039) is gratefully acknowledged.

1,10-Sulfonyl Bisaziridines
REFERENCES
2305
1. Kump, J. E. G. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 7, p. 469.
2. Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599.
3. Dureault, A.; Tranchepain, I.; Depezay, J-C. J. Org. Chem. 1989, 4, 5324.
4. Hudlicky, T.; Luna, H.; Price, J. D.; Rulin, F. J. Org. Chem. 1990, 55, 4683.
5. Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic Chemistry; Pergamon
Press: Oxford, 1984; Vol. 7, p. 47.
6. Maanem, M. J.; Smeets, C. J.; Beijnen, J. H. Cancer Treat Rev. 2000, 26, 257.
7. Voronkov, M. G.; Fedotova, L. A.; Rinkis, D. O. Chem. Heterocycl. Compd. (Engl.
Transl.) 1965, 1, 488.
8. Voronkov, M. G.; Fedotova, L. A.; Rinkis, D. O. Chem. Heterocycl. Compd. (Engl.
Transl.) 1965, 1, 538.
9. Dougherty, J. M.; Probst, D. A.; Robinson, R. E.; Moore, J. D.; Klein, T. A.;
Snelgrove, K. A.; Hanson, P. L. Tetrahedron 2000, 56, 9781.