Asymmetric aziridination: A new entry to optically active non-N-protected aziridines

Article abstract of DOI:10.1016/j.tetlet.2005.12.124

A newly designed robust Ru(salen)(CO) complex 3 was found to catalyze asymmetric aziridination using azide compounds carrying p-nitrobenzenesulfonyl and 2-(trimethylsilyl)ethanesulfonyl (SES) groups, which are easily removable N-protecting groups under mild conditions, as a nitrene precursor in a highly enantioselective manner. In particular, the reactions with SES azide showed excellent enantioselectivity greater than 90% ee, except for one example.

Full text of DOI:10.1016/j.tetlet.2005.12.124

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1571–1574
Asymmetric aziridination: a new entry to optically active
non-N-protected aziridines
Hirotoshi Kawabata, Kazufumi Omura and Tsutomu Katsuki*
Department of Chemistry, Faculty of Science, Graduate School, Kyushu University 33, Hakozaki, Higashi-ku,
Fukuoka 812-8581, Japan
CREST, Japan Science and Technology Agency (JST), Japan
Received 12 December 2005; accepted 28 December 2005
Available online 19 January 2006
Abstract—A newly designed robust Ru(salen)(CO) complex 3 was found to catalyze asymmetric aziridination using azide com-
pounds carrying p-nitrobenzenesulfonyl and 2-(trimethylsilyl)ethanesulfonyl (SES) groups, which are easily removable N-protecting
groups under mild conditions, as a nitrene precursor in a highly enantioselective manner. In particular, the reactions with SES azide
showed excellent enantioselectivity greater than 90% ee, except for one example.
Ó 2006 Elsevier Ltd. All rights reserved.
Achievement of high selectivity and mild reaction condi-
tions as well as realization of environmental benignity
and high atom economy is a key issue in current chem-
ical transformation. Since most organic compounds car-
ry nitrogen functional group(s), C–N bond formation is
a very important transformation for organic synthesis.
Of many C–N bond formations, aziridination is extre-
mely important, because aziridines, especially N-sul-
fonylated ones, undergo various nucleophilic ring-open-
ing reactions due to their high reactivity and serve as
potent synthetic intermediates for nitrogen-containing
compounds.1 Thus, much effort has been devoted to-
ward the development of asymmetric aziridination with
nitrene precursors possessing N-arylsulfonyl group and
many highly enantioselective reactions have been
reported to date.2 However, most of them use N-aryl-
sulfonyliminophenyliodinanes as the nitrene precursor
and the atom economics and ecological benignity of
those reactions remain at an unsatisfactory level,
because a stoichiometric amount of iodobenzene was
inevitably produced as the waste co-product.3 Taking
into consideration the above problems, aziridination
using arylsulfonyl azides as precursor has been continu-
ously studied, because it generates innocuous nitrogen
as the only side product.4 Although asymmetric aziridin-
ation using the azide compound in the presence of a cop-
per or rhodium complex had also been reported, it needs
UV irradiation to decompose the azide compound and it
is modestly enantioselective.5 We recently found that
Ru(salen)(CO) complex 1 catalyzed asymmetric imida-
tion of sulfides6a,b and aziridination6c using azide com-
pounds without UV irradiation at room temperature
in a highly enantioselective manner, but the turnover
number (TON) of the catalyst in the aziridination of
styrene was moderate (Scheme 1). The insufficient
catalyst
NSO2R
+
RSO2N3
Ph
MS 4A, CH2Cl2, rt
Ph
1 (2 mol%), R =
2 (0.09 mol%), R =
2 (1 mol%), R = -O2NC6H4: 84% ee, 34% (TON = 34)
3 (0.1 mol%), R =
p
-CH3C6H4: 87% ee, 71% (TON = 36)
p-CH3C6H4: 85% ee, 78% (TON = 867)
p
p-CH3C6H4: 86% ee, 93% (TON = 982)
1: Ar = Ph
2: Ar = 3,5-F2-4-CH3C6H2
(
R)
CO
3: Ar = 3,5-Cl2-4-(CH3)3SiC6H2
N
O
N
Ru
O
Ar
Ar
3
3'
(aR)
Keywords: Ru(salen)(CO) complex; Asymmetric catalysis; Aziridin-
ation; Azide compound.
*
Corresponding author. Fax: +81 92 642 2607; e-mail: katsuscc@
mbox.nc.kyushu-u.ac.jp
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.124

1572
H. Kawabata et al. / Tetrahedron Letters 47 (2006) 1571–1574
TON was attributed to an undesired intramolecular C–
H insertion reaction of an intermediary azide–Ru spe-
cies, in which the phenyl substituent of the C3- or C30-
naphthyl group was aminated to give a catalytically
inactive species.7 This knowledge prompted us to syn-
thesize catalyst 2 that has a 3,5-difluoro-4-methylphenyl
substituent instead of the phenyl substituent.8 The TON
of 2 in aziridination amounted to 867, when p-toluene-
sulfonyl azide (TsN3) was used as the precursor. How-
ever, removal of the N-protecting simple arylsulfonyl
group needs harsh conditions. This diminishes the utility
of this aziridination. On the other hand, it has been
reported that N-p-nitro- and o-nitro-benzenesulfonyl
(o- and p-Ns)9 and 2-(trimethylsilyl)ethanesulfonyl
(SES)10 groups can be removed under mild conditions.
Complex 2 also catalyzed aziridination using p-nitro-
benzenesulfonyl azide with high enantioselectivity, but
its TON was moderate (36) (Scheme 1). Though the mech-
anism of degradation of 2 was unclear, we speculated that
the o-carbon or p-methyl group might be aminated.
Therefore, we expected that a more robust catalyst could
be constructed, if the two positions are somehow pro-
tected from the amination. Based on this idea, we at-
tempted introducing a pentafluorophenyl group instead
of the phenyl substituent. However, the desired complex
could not be synthesized. Thus, we synthesized a new
complex 3 that possessed a phenyl substituent bearing
chloro and trimethylsilyl groups at its m- and p-positions,
respectively. A bulky chloro substituent was expected to
block its o-hydrogen atom more efficiently than the fluoro
substituent. Aldehyde 6, which was necessary for the syn-
thesis of 3, was prepared from (aR)-iodobinaphthyl 4 in
four steps: (i) Suzuki–Miyaura coupling, (ii) trimethyl-
silylation, (iii) o-directed formylation, and (iv) deprotec-
tion (Scheme 2).8 Condensation of 6 with (1R,2R)-1,2-
cyclohexanediamine sulfate in the presence of K2CO3
and the treatment of the resulting salen ligand with
Ru3(CO)12 in ethanol yielded complex 3.
OMOM
I
OMOM
Ar
a, b
(aR)
With 3 in hand, we first examined aziridination of sty-
rene using TsN3 at room temperature to evaluate its
robustness (Scheme 1). The reaction proceeded with
enantioselectivity of 86% ee similar to those obtained
with 1 or 2 and the TON of 3 amounted to 982.
4
5: Ar = 3,5-Cl2-4-(CH3)3SiC6H2
CHO
Encouraged by this result, we next examined aziridin-
ation of styrene with p-Ns azide in the presence of
0.1 mol % of complex 3. To our delight, TON of 3 was
found to be as large as 746 together with good enantio-
selectivity of 81% ee (Table 1, entry 1). The reaction with
1 mol % of 3 at 0 °C showed somewhat better enantio-
selectivity at the expense of TON, though it was still
as high as 97 (entry 2). Aziridination of other terminal
conjugated olefins also proceeded with high enantiose-
lectivity (entries 3 and 4). However, the reaction of
non-conjugated 1-octene was sluggish at 0 °C and slow
even at elevated temperature, and the enantioselectivity
was moderate (entry 5). We also examined aziridination
OH
c, d
e, f
Ar
3
6
Scheme 2. Reagents and conditions: (a) Pd(PPh3)4 (5 mol %), 3,5-
dichlorobenzeneboronic acid, toluene, 1 M Na2CO3, 100 °C, 92%; (b)
sec-BuLi, THF, ꢀ78 °C, then (CH3)3SiCl, 64%; (c) n-BuLi, N,N,N0,N0-
tetramethylethylenediamine, ꢀ78 °C, then DMF, 84%; (d) HCl/
i-PrOH (20 w/w%), THF, 99%; (e) (1R,2R)-1,2-diaminocyclohexane
sulfate, K2CO3, EtOH, 95%; (f) Ru3(CO)12, EtOH, reflux, 62%.
Table 1. Asymmetric aziridination of various olefins with p-NsN3, o-NsN3, or SESN3 catalyzed by Ru(salen)(CO) 3
Entry
Azide
Catalyst/mol %
R or substrate
Temp/°C
Time/h
Yield/%a
% eeb
TONc
1
2
3
4
5
6
7
8
p-NsN3
p-NsN3
p-NsN3
p-NsN3
p-NsN3
o-NsN3
o-NsN3
o-NsN3
SESN3
SESN3
SESN3
SESN3
SESN3
SESN3
SESN3
0.1
1
1
1
2
0.1
1
1
0.1
1
1
Ph
Ph
4-BrC6H4
PhC„CA
1-Octene
Ph
Ph
PhC„CA
Ph
Ph
Ph
rt
0
0
0
Reflux
rt
0
rt
rt
rt
0
0
38
12
12
12
38
12
12
12
12
12
12
12
12
38
38
70
90
93
81
87
83
98
56
73
81
87
91
90
92
92
>99
77d
98
746
97
94
99
16
660
68
59
260
—
99
98
51
6
98
32c
62
60
58
26
100
99
9
10
11
12
13
14
15
1
1
5
5
4-BrC6H4
PhC„CA
1-Octene
Indene
76
0
50
Reflux
Reflux
28c
47
26
a Isolated yield after silica gel chromatography, unless otherwise mentioned.
b Determined by HPLC analysis.
c Calculated according to 1H NMR analysis.
d Determined by chiral HPLC analysis after the conversion into 2-naphthylsulfide derivative (Ref. 13).

H. Kawabata et al. / Tetrahedron Letters 47 (2006) 1571–1574
1573
Commun. 2002, 124; (c) Lai, T.-S.; Kwong, H.-L.;
Che, C.-M.; Peng, S.-M. Chem. Commun. 1997, 2373; (d)
Noda, K.; Hosoya, N.; Irie, R.; Ito, Y.; Katsuki, T. Synlett
1993, 469; (e) Nishikori, H.; Katsuki, T. Tetrahedron Lett.
1996, 37, 9245; (f) Minakata, S.; Ando, T.; Nishimura, M.;
Ryu, I.; Komatsu, K. Angew. Chem., Int. Ed. 1998, 37,
3392; (g) Nishimura, M.; Minakata, S.; Takahashi, T.;
Oderaotoshi, Y.; Komatsu, M. J. Org. Chem. 2002, 67,
2101; (h) Ho, C.-H.; Lau, T.-C.; Kwong, H.-L.; Wong, W.-
T. J. Chem. Soc., Dalton Trans. 1999, 2411; (i) Evans, D.
A.; Woerpel, K. A.; Hinman, N. M.; Faul, M. M. J. Am.
Chem. Soc. 1991, 113, 726; (j) Evans, D. A.; Faul, M. M.;
Bilodeau, M. T.; Anderson, B. A.; Barnes, D. M. J. Am.
Chem. Soc. 1993, 115, 5328; (k) So¨dergren, M. J.; Alonso,
D. A.; Andersson, P. G. Tetrahedron: Asymmetry 1997, 8,
3563; (l) Tayler, S.; Gullick, J.; Mcmorn, P.; Bethell, D.;
Page, P. C. B.; Hanock, F. E.; King, F.; Hutichings, G. J. J.
Chem. Soc., Perkin. Trans. 2 2001, 1714; (m) Gullick, J.;
Taylor, S.; Ryan, D.; McMorn, P.; Coogan, M.; Bethell,
D.; Page, P. C. B.; Hancock, F. E.; King, F.; Hutchings, G.
J. Chem. Commun. 2003, 2808; (n) Taylor, S.; Gullick, J.;
Galea, N.; McMorn, P.; Bethell, D.; Page, P. C. B.;
Hancock, F. E.; King, F.; Willock, D. J.; Hutchings, G. J.
Top. Catal. 2003, 25, 81; (o) Taylor, S.; Gullick, J.;
McMorn, P.; Bethell, D.; Page, P. C. B.; Hancock, F. E.;
King, F.; Hutchings, G. J. Top. Catal. 2003, 24, 43; (p) Xu,
J.; Ma, L.; Jiao, P. Chem. Commun. 2004, 1616; (q) Ryan,
D.; McMorn, P.; Bethell, D.; Hutchings, G. J. Org. Biomol.
Chem. 2004, 2, 3566; (r) Krumper, J. R.; Gerisch, M.; Suh,
J. M.; Bergman, R. G.; Tilley, T. D. J. Org. Chem. 2003, 68,
9705; (s) Li, Z.; Conser, K. R.; Jacobsen, E. N. J. Am.
Chem. Soc. 1993, 115, 5326; (t) Sanders, C. J.; Gillespie, K.
M.; Bell, D.; Scott, P. J. Am. Chem. Soc. 2000, 122, 7132;
(u) Gillespie, K. M.; Crust, E. J.; Deeth, R. J.; Scott, P.
Chem. Commun. 2001, 785; (v) Gillespie, K. M.; Sanders,
C. J.; O’Shaughnessy, P.; Westmoreland, I.; Thickitt, C. P.;
Scott, P. J. Org. Chem. 2002, 67, 3450; (w) Shi, M.; Wang,
C.-J.; Chan, A. S. C. Tetrahedron: Asymmetry 2001, 12,
3105; (x) Shi, M.; Wang, C.-H. Chirality 2002, 14, 412; (y)
Suga, H.; Kakehi, A.; Ito, S.; Ibata, T.; Fudo, T.;
Watanabe, Y.; Kinoshita, Y. Bull. Chem. Soc. Jpn. 2003,
76, 189; (z) Cho, D.-J.; Jeon, S.-J.; Kim, H.-S.; Cho, C.-S.;
Shim, S.-C.; Kim, T.-J. Tetrahedron: Asymmetry 1999, 10,
3833.
with o-Ns azide. It was found that this azide was less
reactive and the reaction with it was somewhat less
selective than that with p-Ns azide (entries 6–8).
Subsequently to this, we examined aziridination using
SES azide with expectation that the reaction with this
azide would show different stereochemistry from that
with o- or p-Ns azide, because alkyl- and aryl-sulfonyl
groups were considered to interact with the salen ligand
differently from each other.11 Fortunately, complex 3
was found to catalyze aziridination using SES azide as
efficiently as the reaction with o- or p-Ns azide. Further-
more, enantioselectivity was improved to some extent,
as compared with the reaction with o- or p-Ns azide
(entries 9–11).12 It should be noted that complexes 1
and 2 were less efficient also for the aziridination with
SES azide: reactions of styrene in the presence of
1 mol % of complex 1 or 2 at room temperature for
12 h afforded the corresponding SES-protected aziridine
in 10% yield (TON = 10) with 89% ee or in 67% yield
(TON = 67) with 88% ee, respectively. The reactions
of other terminal conjugated olefins with SES azide also
proceeded with high enantioselectivity (entries 12 and
13). The aziridination of 1-octene was slow even at ele-
vated temperature, but it showed good enantioselectivity
of 77% ee (entry 14). The reaction of indene proceeded
with excellent selectivity, albeit with moderate TON (en-
try 15). The N-SES group can be deprotected under mild
conditions and it has been reported that chiral N-SES-
protecting aziridines can be converted to the corre-
sponding aziridines without diminishing their enantio-
meric purity.3g
In conclusion, we were able to achieve highly enantio-
selective aziridination using 2-(trimethylsilyl)ethanesul-
fonyl azide as the nitrene precursor with reasonably
designed Ru(salen)(CO) complex 3 as catalyst. Since the
N-SES group can be readily removed, the present reaction
provides a useful method not only for synthesizing
N-sulfonylated aziridines but also for preparing non-N-
protected ones under mild conditions.
4. For aziridination: Kwart, H.; Khan, A. A. J. Am. Chem.
Soc. 1967, 89, 1951; For sulfimidation: (a) Bach, T.;
Ko¨rber, C. Eur. J. Org. Chem. 1999, 1033; (b) Bach, T.;
Ko¨rber, C. J. Org. Chem. 2000, 65, 2358; (c) Okamura, H.;
Bolm, C. Org. Lett. 2004, 6, 1305; For C–H amination: (d)
Cenini, S.; Tollari, S.; Penoni, A.; Cereda, C. J. Mol.
Catal. A: Chem. 1999, 137, 135; (e) Ragaini, F.; Penoni,
A.; Gallo, E.; Tollari, S.; Gotti, C. L.; Lapadula, M.;
Mangioni, E.; Cenini, S. Chem. Eur. J. 2003, 9, 249.
5. (a) Li, Z.; Quan, R. W.; Jacobsen, E. N. J. Am. Chem. Soc.
Acknowledgments
H.K. is grateful to the Japan Society for the Promotion
of Science (JSPS) Research Fellowships for Young
Scientists.
1995, 117, 5889; (b) Muller, P.; Baud, C.; Na¨geli, I. J.
¨
References and notes
Phys. Org. Chem. 1998, 11, 597; (c) Muller, P.; Baud, C.;
¨
Jacquier, Y. Can. J. Chem. 1998, 76, 738.
6. (a) Murakami, M.; Uchida, T.; Katsuki, T. Tetrahedron
Lett. 2001, 42, 7071; (b) Murakami, M.; Uchida, T.; Saito,
B.; Katsuki, T. Chirality 2003, 15, 116; (c) Omura, K.;
Murakami, M.; Uchida, T.; Irie, R.; Katsuki, T. Chem.
Lett. 2003, 32, 354.
1. For a recent review, see: Hu, X. E. Tetrahedron 2004, 60,
2701.
2. For reviews, see: (a) Jacobsen, E. N. In Comprehensive
Asymmetric Catalysis II; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Chapter 17, p
607; (b) Katsuki, T. In Comprehensive Coordination
Chemistry II; McCleverty, J., Ed.; Elsevier Science Ltd.:
7. Uchida, T.; Tamura, Y.; Ohba, M.; Katsuki, T. Tetra-
hedron Lett. 2003, 44, 7965.
Oxford, 2003; Vol. 9, Chapter 9.4, p 207; (c) Muller, P.;
¨
Fruit, C. Chem. Rev. 2003, 103, 2905; (d) Tanner, D.
Angew. Chem., Int. Ed. Engl. 1994, 33, 599.
8. Omura, K.; Uchida, T.; Irie, R.; Katsuki, T. Chem.
Commun. 2004, 2060.
9. (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron
Lett. 1995, 36, 6373; (b) Fukuyama, T.; Cheung, M.; Jow,
C.-K.; Hidai, Y.; Kan, T. Tetrahedron Lett. 1997, 38, 5831.
3. (a) Kohmura, Y.; Katsuki, T. Tetrahedron Lett. 2001, 42,
3339; (b) Liang, J.-L.; Yu, X.-Q.; Che, C.-M. Chem.

1574
H. Kawabata et al. / Tetrahedron Letters 47 (2006) 1571–1574
10. (a) Weinreb, S. M.; Demko, D. M.; Lessen, A. Tetra-
hedron Lett. 1986, 27, 2099; (b) Weinreb, S. M.; Chase, C.
E.; Wipf, P.; Venkatraman, S. Org. Synth. 1998, 75,
161.
11. For the aziridination using SESN=IPh, see: Dauban, P.;
Dodd, R. H. J. Org. Chem. 1999, 64, 5304.
temperature, SES azide (9.6 lL, 0.05 mmol) was added to
the suspension at 0 °C and stirred for another 12 h at the
temperature. The reaction mixture was filtrated through a
Celite pad and evaporated. TON of Ru(salen) complex 3
was determined by 1H NMR (400 MHz) analysis of the
filtrate. Then, the filtrate was chromatographed on silica
gel (hexane–ethyl acetate = 10/1–5/1) to give N-[2-(tri-
methylsilyl)ethanesulfonyl]-2-phenylaziridine in 99% yield
(92% ee). The enantiomeric excess was determined by
HPLC analysis using DAICEL CHIRALCEL OJ-H
(hexane–i-PrOH = 97/3, 1.0 mL/min, tmajor = 17.8 min
and tminor = 28.0 min).
12. Typical procedure for enantioselective aziridination of
styrene with SES azide: Ru(salen)(CO) complex 3 (0.6 mg,
0.5 lmol) was dried twice by azeotropical concentration of
its toluene solution (0.25 mL) in vacuo under nitrogen
˚
atmosphere. Then, MS 4 A (10 mg), styrene (5.7 lL,
0.05 mmol), 2-bromonaphthalene (2.0 mg, as the internal
standard), and dichloromethane (0.25 mL) were added to
the dried complex 3. After stirring for 0.5 h at room
13. Kim, S. K.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2004,
43, 3952.