One-pot and microwave-assisted synthesis of N-sulfonylaziridines

Article abstract of DOI:10.1016/j.tetlet.2011.03.106

A novel and efficient microwave-assisted one-step reaction was developed to synthesize chiral N-sulfonylaziridines by the reaction of different chiral amino alcohols and sulfonic chlorides. The newly developed microwave synthetic method has the advantage of reducing the reaction time from 24 to 0.5 h with improved yields (84-93%) and minimizing by-products.

Full text of DOI:10.1016/j.tetlet.2011.03.106

Tetrahedron Letters 52 (2011) 2873–2875
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot and microwave-assisted synthesis of N-sulfonylaziridines
Hao Xu a, Hua Tian a, Liangyu Zheng b, , Qingwen Liu a, Li Wang a, Suoqin Zhang a,
⇑
⇑
a College of Chemistry, Jilin University, Changchun 130012, PR China
b Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Jilin University, Changchun 130012, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient microwave-assisted one-step reaction was developed to synthesize chiral N-sulf-
onylaziridines by the reaction of different chiral amino alcohols and sulfonic chlorides. The newly devel-
oped microwave synthetic method has the advantage of reducing the reaction time from 24 to 0.5 h with
improved yields (84–93%) and minimizing by-products.
Received 23 December 2010
Revised 18 March 2011
Accepted 25 March 2011
Available online 1 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
N-sulfonylaziridines
Microwave synthesis
One-pot reaction
Chiral amino alcohol
Aziridines as building blocks1 and chemical reagents2 are
important functional compounds in organic synthesis. The applica-
tion of enantiomerically enriched aziridines as asymmetric syn-
thetic intermediates continues to enjoy widespread exposure in
asymmetric organic synthesis. In analogy to epoxides, enantiome-
rically enriched aziridines react with different nucleophiles, via
ring opening reactions, allowing the introduction of a chiral
ethylamino group in a wide range of substrates.3,4 In particular,
chiral N-sulfonylaziridines, as reagents for chemical fixation of
CO2,5 as ligands6,7 and as precursors of many synthetic targets,4f,g
are much more important.
be obtained in good yields by phase-transfer catalysts at the first
time. In 2009 Groeper15 demonstrated that other sulfonyl groups,
such as camphorslfonyl chloride, could be used in the synthesis
of N-sulfonylaziridines.
However, in these methods synthesis of N-sulfonyl aziridines
needed more steps, longer time (12–48 h), much lower tempera-
ture (À78 to À50 °C), or special reagents such as Aliquat 336 or
camphorslfonyl chloride. Up to date aziridines have not been pre-
pared effectively via one-pot reaction from amino alcohols and sul-
fonic chlorides, probably due to the fact that other by-products are
competitive with the main products in the cyclization reaction.
Herein, based on the study of the main by-product, we report a
novel and efficient microwave-assisted one-pot reaction that was
developed to synthesize chiral N-sulfonylaziridines from different
chiral amino alcohols and sulfonic chlorides. When microwave
(MW) irradiation was used in the reactions, the ring-closure reac-
tion time was shortened and the main by-products were
minimized.
Due to the importance of chiral N-sulfonylaziridines, consider-
able efforts have been devoted to their synthesis. N-sulfonylaziri-
dines have been prepared from b-hydroxy-a-animoe-sters by
intramolecular cyclization,6,7 from N,O-disulfonyl derivatives8
and N-trityl-O-tosyl derivatives by ring closure,4e,9 and from al-
kenes via nitrene insertion.10 In 1992 Craig and Berry11 employed
a three-step process to synthesize aziridines from commercially
available chiral amino acids. In 2003 Leighton and Krauss12 dem-
onstrated that aziridines could be prepared by a more effective,
Chiral amino alcohols (2a–2d) were obtained in excellent yields
by the reaction of commercially available chiral amino acids (1a–
1d) with an excess of LiAlH4 in THF. Chiral amino alcohol (2e)
was obtained by the esterification of commercially available L-ser-
ine (1e) with sulfoxide chloride (SOCl2) in methanol.
one-step sequence from either L-valinol or L-tert-leucinol. In 2004
Zhang13 prepared N-sulfonylaziridines via the aziridination of
tras-b-methylstyrene using iron as a catalyst.
Even though many syntheses of N-sulfonylaziridines have been
reported, the exploration of new methods has been very active in
recent years. In 2007, Marzorati and Vitta14 refined this process
so that such N-sulfonylaziridines with withdrawing groups could
Under microwave irradiation and different solvents conditions,
compound 2a can also be converted into N-tosylaziridines 3a with
high yields at higher temperature (40 °C), however, it is not
possible to isolate 3a when the reaction is carried out without
microwave irradiation, but instead only other by-products. Via
complete characterizations by spectral methods, the main by-
product was confirmed as a six-member ring compound (4a)
(Scheme 1). To minimize 4a, we submitted chiral amino alcohol
⇑
Corresponding authors. Tel.: +86 431 85155252; fax: +86 431 85168420 (L.Z.);
tel.: +86 431 85168468; fax: +86 431 85168420 (S.Z.).
E-mail addresses: lyzheng@jlu.edu.cn (L. Zheng), suoqin@jlu.edu.cn (S. Zhang).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.106

2874
H. Xu et al. / Tetrahedron Letters 52 (2011) 2873–2875
Table 2
Ts
Preparation of N-tosylaziridinesa (3a–3e)
OH
+
TsCl
+
N
NH2
R
MW
OH
NH2
Ts
N Ts
Ts
4a
TsCl
+
DCM/DMAP
2a
3a
R
5d
3a-3e
2a-2e
5d
Scheme 1. The reaction of tosyl chloride and valinol.
Entry
Amino alcohol
Base
Time (h)
Yieldb (%)
(2a) to react with tosyl chloride, inorganic bases, and 4-dimethyl-
aminopyridine (DMAP) in dichloromethane (DCM) under micro-
wave irradiation. When the reaction was performed after 30 min,
only one new spot was observed by TLC (ethyl acetate/petroleum
ether = 1:6, Rf = 0.45). Complete characterizations by spectral
methods confirmed the product as N-tosyl-2-benzlyaziridine
(3a).16 The ring closure reaction was completed as expected under
microwave irradiation.
The results of the synthesis of N-tosyl-2-benzlyaziridine 3a
from the Valinol (2a) in different reaction conditions are summa-
rized in Table 1. When the reaction was performed at 40 °C with
DMAP and K2CO3 in dichloromethane, product 3a was obtained
in good yields in 30 min. When the reaction was performed in
other solvents (THF, MeCN, diethyl ether), the results were reason-
able. Via altering different inorganic and organic bases, such as
K2CO3, Na2CO3, Cs2CO3, NaOH, and TEA, the excellent results were
obtained, when K2CO3 and Cs2CO3 were applied in the reaction.
Under microwave irradiation 4a was scarcely observed, probably
due to the fact that intramolecular cyclization was much more
favorable than intermolecular reaction under the microwave irra-
diation condition. Compared to the previous reported methods
which needed 16–48 h11,12 or special reagents14,15 for the synthesis
of N-tosylaziridines from amino alcohols and sulfonic chlorides in
reasonable yields, the present one-pot microwave assisted cycliza-
tion reaction is much more efficient.
1
2
3
2a
2b
2c
2d
2e
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
0.5
0.5
0.5
0.5
1
93
93
89
88
90
4
5c
2a: valinol; 2b:
ester.
L
-phenylalaninol; 2c:
L
-leucinol; 2d:
L
-alaninol; 2e:
L
-serine methyl
a
Conditions: the reaction were preformed at 40 °C, in DCM, under microwave
irradiation (400 W), 20% DMAP.
b
Isolated yield.
Without DMAP.
c
dine-2-carboxylate (3e) was only obtained in a reasonable yield
(54%) in previous reports. When 3e was synthesized according to
the new one-pot method under the same condition as 3a, numer-
ous by-products occurred. The possible reason is that DMAP could
activate the acyl groups, which resulted in the side-reactions
occurring. However, the synthesis of (2S)-1-[(4-methylphenyl)sul-
fonyl]aziridine-2-carboxylate (3e) was also explored in a higher
yield (90%) in 60 min under microwave irradiation without DMAP.
Enantiomerically pure N-tosylaziridines from chiral amino alco-
hols should be obtained if racemization does not occur in the con-
version. Thus, the specific rotation of all the products (3a–3e) was
determined. Compared to the reported specific rotation, the
N-tosylaziridines of >98% ee were obtained. The results confirmed
that racemization was avoided under microwave irradiation.
For demonstrating that the method is extensive, other sulfonic
chlorides have been used to react with chiral amino alcohols to
perform the intramolecular cyclization. The results are summa-
rized in Table 3. With more active sulfonic chlorides (5a–5b), azir-
idines were obtained in high yields. When chiral amino alcohols
were converted into aziridines via the reactions with inactive sul-
The successful cyclization of Valinol (2a) encouraged us to ex-
plore more chiral amino alcohols (2b–2e). The results are summa-
rized in Table 2. As expected, N-tosylaziridines (3b–3e) were
obtained in 30 mins in good yields (88–93%). Methyl (2S)-1-
[(4-methylphenyl)sulfonyl]aziridine-2-carboxylate (3e), including
an electron withdrawing group, was more difficult to be synthesized
than other analogues with an electron donating group using the re-
ported methods.14 Though different phase-transfer catalysts were
applied in the reaction, (2S)-1-[(4-methylphenyl)sulfonyl]aziri-
Table 3
Preparation of N-sulfonylaziridines via the reaction of sulfonic chlorides and amino
alcoholsa
O
Cl
O S O
R1
MW
R
Table 1
OH
NH2
N S R1
O
+
Preparation of N-tosylaziridinea (3a)
DCM/DMAP
R
Ts
3f-3i
5a-5c
MW
N
OH
TsCl
+
+
Ts
N
N
NH2
DCM/DMAP
Ts
4a
Entry
Sulfonic chloride
Amino alcohol
Time (h)
Yieldc,e (%)
3a
2a
5d
1
5a
5b
5b
5c
5a
5b
5b
5c
2b
2b
2e
2b
2b
2b
2e
2b
0.5
0.5
1
84 (3f)
89 (3g)
65 (3h)
88 (3i)
75 (3f)
48 (3g)
—
2
3d
4
Entry
Solvent
Base
K2CO3
Time (h)
Yield (%) 3ab
Yield (%) 4ab
1
5b
6b
7b,d
8b
96
96
96
96
1
2
3
4
5c
6
7
8
9
Diethyl ether
THF
0.5
0.5
0.5
0.5
96
2
0.5
0.5
1
91
87
89
93
69
48
92
85
80
Trace
10
Trace
—
26
—
—
—
Trace
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
NaOH
TEA
MeCN
DCM
DCM
DCM
DCM
39 (3i)
a: R 1 = methyl, b: R1 = phenyl, c: R1 = 4-methoxyphenyl.
a
Conditions: the reactions were preformed at 40 °C, in DCM, under microwave
irradiation (400 w), 20% DMAP.
DCM
DCM
b
Without microwave irradiation.
Isolated yield.
Without DMAP.
c
a
d
Conditions: the reaction were preformed at 40 °C, in DCM, under microwave
e
irradiation (400 W), 20% DMAP.
HPLC was used for determination. For analysis of 3f–3i: Chiralcel OD-H,
n-hexane/isopropyl alcohol = 95:5. The racemizations of products were not
observed under microwave irradiation, and 3f–3i of >99% ee were obtained.
b
Isolated yield.
c
Without microwave irradiation.

H. Xu et al. / Tetrahedron Letters 52 (2011) 2873–2875
2875
Davis, F. A. Synthesis 2000, 1347; (g) Hu, X. E. Tetrahedron 2004, 60, 2701; (h)
Cardillo, G.; Gentilucci, L.; Tolomelli, A. Aldrichim. Acta. 2003, 36, 39.
5. Sudo, A.; Morioka, Y.; Sanda, F.; Endo, T. Tetrahedron Lett. 2004, 45, 1363.
6. Tanner, D.; Harden, A.; Johansson, F.; Wyatt, P.; Andersson, P. G. Acta Chem.
Scand. 1996, 50, 361.
7. (a) Tanner, D.; Birgersson, C.; Dhaliwal, H. K. Tetrahedron Lett. 1990, 31, 1903;
(b) Fujii, N.; Nakai, K.; Habashita, H.; Hotta, Y.; Tamamura, H.; Otaka, A.; Ibuka,
T. Chem. Pharm. Bull. 1994, 42, 2241; (c) Solomon, M. E.; Lynch, C. L.; Rich, D. H.
Synth. Commun. 1996, 26, 2723.
8. (a) Nakagawa, Y.; Tsuno, T.; Nakagima, K.; Iwai, M.; Kawai, H.; Okawa, K. Bull.
Chem. Soc. Jpn. 1972, 45, 1162; (b) Imae, K.; Kamachi, H.; Yamashita, H.; Okita,
T.; Okuyama, S.; Tsuno, T.; Yamasaki, T.; Sauada, Y.; Ohbayashi, M.; Naito, T.;
Oki, T. J. Antibiot. 1991, 44, 76.
9. Baldwin, J. E.; Spivey, A. C.; Schofield, C. J.; Sweeney, J. B. Tetrahedron 1993, 49,
6309.
10. (a) Li, Z.; Conser, K. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1993, 115, 5326; (b)
Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.; Barnes, D. M. J. Am.
Chem. Soc. 1993, 115, 5328; (c) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Am.
Chem. Soc. 1994, 116, 2742; (d) Li, Z.; Quan, R. W.; Jacobsen, E. N. J. Am. Chem.
Soc. 1995, 117, 5889; (e) Gillespie, K. M.; Sanders, C. J.; O’Shaughnessy, P.;
Westmoreland, I.; Thickitt, C. P.; Scott, P. J. Org. Chem. 2002, 67, 3450; (f) Jain, S.
L.; Sain, B. Tetrahedron Lett. 2003, 44, 575; (g) Chanda, B. M.; Vyas, R.; Landge, S.
S. J. Mol. Catal. A: Chem. 2004, 223, 57.
fonic chlorides (5c), which have not been reported in previous re-
ports, aziridines were also obtained easily in 60 min. The results
suggest that N-sulfonylaziridines with active or inactive sulfonyl
groups were easily prepared under microwave irradiation.
In summary, the cyclization reaction of chiral amino alcohols
and sulfonic chlorides under microwave irradiation is an efficient
one-pot procedure to prepare chiral N-sulfonylaziridines. It is
applicable to synthesize N-sulfonylaziridines by the reaction of
readily available b-hydroxy-a-animo derivatives with electron
withdrawing groups or electron donating groups and active sul-
fonic chlorides or inactive sulfonic chlorides. The conditions of
the cyclization reactions were optimized in different solvents with
inorganic or organic bases. The reactions by using microwave irra-
diation gave the object products in a better yield (84–93%) in
shorter time with higher purity.
Acknowledgments
11. Berry, M. B.; Craig, D. Synlett 1992, 41.
12. Krauss, I. J.; Leighton, J. L. Org. Lett. 2003, 5, 3201.
13. (a) Vyas, R.; Gao, G. Y.; Harden, J. D.; Zhang, X. P. Org. Lett. 2004, 6, 1907; (b)
Han, H.; Park, S. B.; Kim, S. K.; Chang, S. J. Org. Chem. 2008, 73, 2862.
14. Marzorati, L.; Barazzone, G. C.; Wladislaw, B.; Vitta, C. D. Tetrahedron Lett. 2007,
48, 6509.
The authors are grateful for the financial support from National
Natural Science Foundation of China (No. 20802025) and Jilin Pro-
vincial Science
&
Technology Sustentation Program (Nos.
20090585 and 20100538).
15. Groeper, J. A.; Eagles, J. B.; Hitchcock, S. R. Tetrahedron: Asymmetry 1969, 2009,
20.
References and notes
16. General procedure for preparation of N-sulfonylaziridines:
A solution of 2a
(0.103 g, 1 mmol) in anhydrous dichloromethane (20 mL) was cooled to 0 °C.
K2CO3 (0.552 g, 4 mmol), DMAP (24.0 mg, 0.2 mmol) and tosyl chloride
(0.416 g, 2.2 mmol) were added to the reaction mixture. The mixture was
stirred under microwave irradiation (400 W) at 40 °C. After 30 min, the
reaction mixture was washed with saturated brine. Organic phase was dried
over anhydrous Na2SO4 and concentrated in vacuum. The crude product was
purified by silica gel column to give 3a (0.209 g, 0.877 mmol, 87.7%) as a white
1. (a) Sweeny, J. B. In Science of Synthesis, 2008, Vol. 40a, 643.; (b) Padwa, A. In
Comprehensive Heterocyclic Chemistry III, 2008, Vol. 1, p. 1.; (c) Coleman, R. S.;
Carpenter, A. J. J. Org. Chem. 1992, 57, 5813; (d) Li, P. X.; Evans, C. D.; Joullié, M.
M. Org. Lett. 2005, 7, 5325; (e) Hanessian, S.; Del Valle, J. R.; Xue, Y. F.;
Blomberg, N. J. Am. Chem. Soc. 2006, 128, 10491; (f) Bergmeier, S. C.; Lee, W. K.;
Rappaport, H. J. Org. Chem. 1993, 58, 5019; (g) Hodgson, D. M.; Štefane, B.;
Miles, T. J.; Witherington, J. J. Org. Chem. 2006, 71, 8510; (h) Denolf, B.;
Leemans, E.; De Kimpe, N. J. Org. Chem. 2007, 72, 3211; (i) Sekar, G.; Singh, V. K.
J. Org. Chem. 1999, 64, 2537; (j) Shao, H.; Zhu, Q.; Goodman, M. J. Org. Chem.
1995, 60, 790; (k) Hsu, J. L.; Fang, J. M. J. Org. Chem. 2001, 66, 8573; (l) Davis, F.
A.; Deng, J. H. Org. Lett. 2007, 9, 1707; (m) Leemans, E.; Mangelinckx, S.;
DeKimpe, N. Synlett 2009, 1265.
2. (a) Bulut, A.; Aslan, A.; Izgü, E. C.; Dogan, Ö. Tetrahedron: Asymmetry 2007, 18,
1013; (b) Isleyen, A.; Dogan, Ö. Tetrahedron: Asymmetry 2007, 18, 679.
3. Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247. and references cited therein.
4. (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599; (b) Atkinson, R. S.
Tetrahedron 1999, 55, 1519; (c) Zwanenburg, B. Top. Curr. Chem. 2001, 216, 93;
(d) Lee, W. K.; Ha, H. J. Aldrichim. Acta 2003, 36, 57; (e) Beresford, K. J. M.;
Church, N. J.; Young, D. W. Org. Biomol. Chem. 2006, 4, 2888; (f) McCoull, W.;
solid. 1H NMR (CDCl3, 300 MHz)
d (ppm) 7.83 (d, J = 8.2 Hz, 2H), 7.34
(d, J = 8.2 Hz, 2H), 2.62 (d, J = 7.0 Hz, 1H), 2.55–2.48 (m, 1H), 2.45 (s, 3H),
2.11 (d, J = 4.6 Hz, 1H), 1.47–1.36 (m, 1H), 0.90 (d, J = 6.8 Hz, 3H), 0.79
(d, J = 6.8 Hz, 3H). MS (ESI) m/z: calcd for (M+H)+ 240, found 240.15. Anal. Calcd
for C12H17NO2S: C, 60.22; H, 7.16; N, 5.85; S, 13.40. Found: C, 60.29; H, 7.14; N,
5.82; S, 13.39. The by-product 4a (trace) was obtained at the same time as a
white solid. 1H NMR (CDCl3, 300 MHz) d (ppm) 7.98 (d, J = 8.0 Hz, 4H), 7.35
(d, J = 8.0 Hz, 4H), 4.46–4.41 (m, 2H), 4.27 (t, J = 8.7 Hz, 2H), 4.15 (dd, J = 9.0,
3.0 Hz, 2H), 2.52–2.43 (m, 8H), 0.93 (d, J = 6.9 Hz, 6H), 0.76 (d, J = 6.9 Hz, 6H).
MS (ESI) m/z: calcd for (M+H)+ 479, found 479.04. Anal. Calcd for
C24H34N2O4S2: C, 60.22; H, 7.16; N, 5.85; S, 13.40. Found: C, 60.27; H, 7.15;
N, 5.81; S, 13.42.