Lewis base catalyzed ring opening of aziridines with silylated nucleophiles

Article abstract of DOI:10.1021/ol051186f

(Chemical Equation Presented) The ring opening of N-tosylaziridines with trimethylsilylated nucleophiles, catalyzed by N,N,N′,N′- tetramethylethylenediamine, led to the production of β-functionalized sulfonamides in good to excellent yields with high regi

Full text of DOI:10.1021/ol051186f

ORGANIC
LETTERS
2005
Vol. 7, No. 16
3509-3512
Lewis Base Catalyzed Ring Opening of
Aziridines with Silylated Nucleophiles
Satoshi Minakata,* Yuriko Okada, Yoji Oderaotoshi, and Mitsuo Komatsu*
Department of Applied Chemistry, Graduate School of Engineering, Osaka UniVersity,
Yamadaoka 2-1, Suita, Osaka 565-0871, Japan
komatsu@chem.eng.osaka-u.ac.jp
Received May 19, 2005
ABSTRACT
The ring opening of N-tosylaziridines with trimethylsilylated nucleophiles, catalyzed by N,N,N′,N′-tetramethylethylenediamine, led to the production
of â-functionalized sulfonamides in good to excellent yields with high regioselectivity.
Aziridines are very useful synthetic intermediates for the
synthesis of functional materials and biologically active
compounds.1 For this reason, in previous studies, we
developed some facile synthetic methods for producing
aziridines through the introduction of an N1 unit to alkenes.2
The reactivity of aziridines toward ring opening and expan-
sion is dependent upon their extremely strained ring struc-
tures. Among the procedures of ring opening of aziridines,
a nucleophilic ring-opening reaction is one of the major
routes to highly functionalized compounds.3 Ring-opening
reactions of aziridines have been developed using silylated
nucleophiles.4 Most of these methods are limited to the use
of heavy and/or inexpensive metal-based catalysts such as a
Lewis acid and frequently result in the formation of mixtures
of regioisomers. Hou and co-workers reported on the ring
opening of aziridines with silylated nucleophiles, triggered
by the presence of tetrabutylammonium fluoride (TBAF).5
In the reaction, ammonium cyanide, derived from trimeth-
ylsilyl cyanide (TMSCN) and TBAF, acts as a nucleophile
for the ring opening. While Lewis acid catalyzed ring-
opening reactions, the regioselectivity of which are difficult
to control, are based on the activation of aziridines, Hou’s
method probably involved the generation of a rather strong
nucleophile (cyanide, azide, etc.) from TMSNu, similar to
(1) (a) Sweeny, J. B. Chem. Soc. ReV. 2002, 31, 247-258. (b) Tanner,
D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599-619. (c) Padwa, A.; Pearson,
W. H.; Lian, B. N.; Bergmeier, S. C. In ComprehensiVe Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F., Eds.;
Pergamon: Oxford, 1996; Vol. 1A, pp 1-60. (d) Padwa, A.; Woolhouse,
A. D. In ComprehensiVe Heterocyclic Chemistry; Lwowski, W., Ed.;
Pergamon: Oxford, 1984; Vol. 7.
(4) (a) Matsubara, S.; Kodama, T.; Utimoto, K. Tetrahedron Lett. 1990,
31, 6379-6380. (b) Leung, W. H.; Yu, M. T.; Wu, M. C.; Yeung, L. L.
Tetrahedron Lett. 1996, 37, 891-892. (c) Ferraris, D.; Drury, W. J., III;
Cox, C.; Lectka, J. J. Org. Chem. 1998, 63, 4568-4569. (d) Li, Z.;
Fernandez, M.; Jacobsen, E. N. Org. Lett. 1999, 1, 1611-1613. (e)
Chandrasekhar, M.; Sekar, G.; Singh, V. K. Tetrahedron Lett. 1990, 31,
6379-6380. (f) Shin, S.-H.; Han, E. Y.; Park, C. S.; Lee, W. K.; Ha, H.-J.
Tetrahedron: Asymmetry 2000, 11, 3293-3301. (g) Yadav, J. S.; Reddy,
B. V. S.; Kumar, G. M.; Murthy, C. V. S. R. Synth Commun. 2000, 32,
1797-1802. (h) Reddy, M. A.; Reddy, L. R.; Bhanumathi, N.; Rao, K. R.
Chem. Lett. 2001, 246-247. (i) Osborn, H. M. I.; Sweeney, J. B. Synlett
1994, 145-147. (j) Chandrasekhar, M.; Sekar, G.; Singh, V. K. Tetrahedron
Lett. 2000, 41, 10079-10083.
(2) (a) Ando, T.; Minakata, S.; Ryu, I.; Komatsu, M. Tetrahedron Lett.
1998, 39, 309-312. (b) Ando, T.; Kano, D.; Minakata, S.; Ryu, I.; Komatsu,
M. Tetrahedron 1998, 54, 13485-13494. (c) Minakata, S.; Ando, T.;
Nishimura, M.; Ryu, I.; Komatsu, M. Angew. Chem., Int. Ed. 1998, 37,
3392-3394. (d) Nishimura, M.; Minakata, S.; Thongchant, S.; Ryu, I.;
Komatsu, M. Tetrahedron Lett. 2000, 41, 7089-7092. (e) Kano, D.;
Minakata, S.; Komatsu, M. J. Chem. Soc., Perkin Trans. 1 2001, 3186-
3188. (f) Nishimura, M.; Minakata, S.; Takahashi, T.; Oderaotoshi, Y.;
Komatsu, M. J. Org. Chem. 2002, 67, 2101-2110. (g) Minakata, S.; Kano,
D.; Fukuoka, R.; Oderaotoshi, Y.; Komatsu, M. Heterocycles 2003, 60,
289-298. (h) Minakata, S.; Kano, D.; Oderaotoshi, Y.: Komatsu, M.
Angew. Chem., Int. Ed. 2004, 43, 79-81.
(5) Wu, J.; Hou, X.-L.; Dai, L.-X. J. Org. Chem. 2000, 65, 1344-1348.
(6) Hosomi, A.; Shirahata, A.; Sakurai, H. Tetrahedron Lett. 1978, 19,
3043-3046.
(3) A recent review, see: Hu, X. E. Tetrahedron 2004, 60, 2701-2743
and references therein.
10.1021/ol051186f CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/02/2005

the Sakurai-Hosomi reaction.6 In an attempt to better control
the regioselectivity of such reactions, we focused on the
activation of silyl reagents with a Lewis base catalyst (Figure
1). Although Mukaiyama and Kobayashi7 originally reported
1,2-dimethoxyethane was not effective, 1,2-bis(dimeth-
ylphosphino)ethane readily promoted the reaction (Table 1,
entries 5 and 6). Tertiary amines and a phosphine were also
found to function as catalysts for the ring opening. Among
these, amines are inexpensive and commercially available
and would be promising reagents for asymmetric reactions
in our future studies. For the above reasons, TMEDA was
selected for use in the ring opening of other aziridines.
The ring opening of 1a was attempted with 20 mol % of
TMEDA at room temperature, using a range of solvents,
including acetonitrile, toluene, dichloromethane, and THF.
Of these, only acetonitrile resulted in a complete conversion
within 24 h. The ring opening of 2-substituted N-tosylaziri-
dines was investigated under optimized conditions, and the
results are shown in Table 2.
Figure 1. Representative modes of the ring opening of aziridines
with TMSNu.
that Lewis bases are good catalysts for the silylcyanation of
aldehydes with TMSCN, there are no examples of the ring
opening of aziridines in which a combination of silyl
compounds and Lewis base catalysts are used. From these
points of view, we report on the Lewis base-catalyzed
regioselective ring opening of aziridines with trimethylsilyl
cyanide, azide, and halides. The resulting products have the
potential for serving as good building blocks for the
preparation of vicinal diamines and â-amino acids.
Although an initial reaction of aziridine 1a with TMSCN
in acetonitrile at room temperature did not proceed at all,
when triethylamine (20 mol %) was added to the system
ring-opening product 2a was obtained in 63% yield after
workup (Table 1, entries 1 and 2). When N-methylpyrrolidine
Table 2. TMEDA-Catalyzed Ring Opening of 2-Substituted
N-Tosylaziridines with TMSCN
entry
aziridine
R
T (°C)
time (h)
yield (%)
1
2
3
4
5b
1a
1b
1c
1d
1e
n-C6H13
CH2Ph
s-C4H9
Ph
rt
rt
60
rt
60
24
24
48
64
18
83 (2a)
84 (2b)
93 (2c)
47a (2d)
88c (2e)
CH2OH
a Recovery of 1d: 19%. b TMSCN: 2 equiv. c Including 48% of
O-silylated ring-opening product (R ) CH2OSiMe3).
Table 1. Lewis Base Catalyzed Ring Opening of an Aziridine
with TMSCN: The Effect of Lewis Bases
As described above, aziridines 1b as well as 1a were
readily converted to the corresponding ring-opening products
in good yields with complete regioselectivity (Table 2, entries
1 and 2). When the reaction of sec-butyl-substituted aziridine
1c was examined at these conditions (rt), the reaction
proceeded rather slowly (70% yield after 120 h, 25%
recovery of 1c). At a temperature of 60 °C, however, the
rate of the reaction increased, affording 2c in 93% yield
(Table 2, entry 3). Although the efficiency of the reaction
of 1d could be improved, a complete regioselective ring
opening was observed (Table 2, entry 4). In the case of
nonmetallic and metal salt-promoted reactions, the product
that opened at the benzylic position was mainly produced
as a mixture of two regioisomers.8 In contrast to this known
behavior, the regioselectivity induced by the present method
is perfect and similar to the case where strong nucleophiles
are used. The method was also found to be applicable to the
a TMEDA: 10 mol %.
(7) Kobayashi, S.; Tsuchiya, Y.; Mukaiyama, T. Chem. Lett. 1991, 537-
540.
(8) For recent examples, see: (a) Hou, X.-L.; Fan, R.-H.; Dai, L.-X. J.
Org. Chem. 2002, 67, 5295-5300. (b) Ding, C.-H.; Dai, L.-X.; Hou, X.-L.
Synlett 2004, 1691-1694. (c) Yadav, J. S.; Reddy, B. V. S.; Baishya, G.;
Reddy, P. V.; Harshavardhan, S. J. Synthesis 2004, 1854-1858. For
successfully controlled examples, see: (d) Wu, J.; Hou, X.-L.; Dai, L.-X.
J. Chem. Soc., Perkin Trans. 1 2001, 1314-1317. (e) Furuta, Y.; Kumamoto,
T.; Ishikawa, T. Synlett 2004, 362-364.
or N,N,N′,N′-tetramethylethylenediamine (TMEDA) was
employed, the starting material was completely consumed
and 2a was produced in good yields (Table 1, entries 3 and
4). Since TMEDA contains two Lewis basic sites, 10 mol
% of the base was used to produce 2a in 76% yield. While
3510
Org. Lett., Vol. 7, No. 16, 2005

ring opening of a hydroxylated compound, giving the
corresponding product, including the O-silylated ring opening
compound, in good yields (Table 2, entry 5).
Table 3. TMEDA-Catalyzed Ring Opening of
2,3-Disubstituted N-Tosylaziridines with TMSCN
With an acceptable result for the ring opening of 2-sub-
stituted aziridines catalyzed by TMEDA in hand, the method
was extended to 2,3-disubstituted aziridines. When the
bicyclic aziridines 1f and 1g were treated with TMSCN in
the presence of TMEDA at 60 °C for 24 h, the yields of the
ring-opening products were moderate, especially for 1g.
Since the starting aziridine 1g was recovered, the progress
of the ring opening of 1g was monitored by 1H NMR (Figure
2). The spectral data indicated that 1g and 2g were present
azir-
entry idine
Me3SiCN
T
time yield
R1
R2
R3 (equiv) (°C) (h)
(%)
1a 1f
2a 1g
1g
4a 1h
H
H
H
H
H
-(CH2)3-
-(CH2)4-
-(CH2)4-
n-C5H11 Me
n-C5H11 Me
1.2
1.2
1.2
1.5
1.5
60 24 70 (2f)
60 24 57b (2g)
60 72 97 (2g)
100 48
80 100 90
(2h, 3h)c
80 100 80
(2i, 3i)c
3
0
5
6
1h
1i
n-C5H11
H
Me
1.5
a Without KCN. b Recovery of 1g: 41%. c Regioisomer ratio: 2h/3h )
67/33; 2i/3i ) 80/20.
and 1g to afford the corresponding products in quantitative
yields (Table 4, entries 7 and 8). The reactions listed in Table
4 did not proceed in the absence of a Lewis base (TMEDA)
at all.
Table 4. TMEDA-Catalyzed Ring Opening of
N-Tosylaziridines with TMSNu
Figure 2. Time course for the ring opening of 1g at 60 °C, without
KCN vs with KCN (1 equiv).
as an equilibrium mixture and, as a logical offshoot, the
addition of KCN improved the efficiency of the reaction,
giving the desired 2g in quantitative yield. Quite recently,
many examples of the ring opening of three-membered
heterocycles have appeared, but reactions of 2,3-dialkyl-
substituted unfused aziridines are rare.9 The ring opening of
2,3-cis-dialkyl-substituted aziridine 1h failed to proceed at
all, even at 100 °C, in the absence of KCN. The presence of
KCN enabled the ring opening of 1h and 1i in good yields,
giving a mixture of regioisomers, where the stereoselectivity
was completely controlled to afford a sole diastereomer
(Table 3).
entry aziridine
R1
R2 Nu T (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1b
1b
1f
n-C6H13
n-C6H13
n-C6H13
CH2Ph
CH2Ph
CH2Ph
H
H
H
H
H
H
N3 rt
Br rt
24
48
24
24
48
48
48
48
90 (4a)
88 (5a)
97 (6a)
88 (4b)
88 (5b)
99 (6b)
97 (4f)
98 (4g)
I
rt
N3 rt
Br rt
I
rt
-(CH2)3-
-(CH2)4-
N3 50
N3 50
1g
This amine-catalyzed reaction of aziridines with TMSCN
is applicable to other silylated nucleophiles, TMSN3 and
TMSX, as shown in Table 4. Alkyl-substituted N-tosylaziri-
dines, such as 1a and 1b, were readily opened by azide,
bromide, and iodide in the presence of a catalytic amount
of TMEDA to give the desired compounds in good yields
(Table 4, entries 1-6).10 Even in the absence of KCN, the
stronger nucleophilicity of the azide ion, compared to that
of cyanide led to the ring opening of bicyclic aziridines 1f
Heterogeneous catalysts immobilized on silica gel have
been developed extensively. Among these, silica gel func-
tionalized with amino groups has proved to be a useful
insoluble catalyst for Knoevenagel condensations,11 the
oxidation of alkanes,12 and Michael addition reactions.13 The
utility associated with the reusability and simple workup
(11) Angeletti, E.; Canepa, C.; Martinetti, G.; Venturello, P. J. Chem.
Soc., Perkin Trans. 1 1989, 105-107.
(12) Kurusu, Y.; Neckers, D. C. J. Org. Chem. 1991, 56, 1981-1983.
(13) Mdoe, J. E. G.; Clark, J. H.; Macquarrie, D. J. Synlett 1998, 625-
627.
(9) For meso-aziridines, see, for example, ref 4h.
(10) While Hou’s method is successfully applicable to the ring opening
of aziridines with TMSCl, ring opening of 1a with the silyl chloride under
the conditions did not proceed at all to recover the starting material.
Org. Lett., Vol. 7, No. 16, 2005
3511

2a was produced in 60% yield in the second cycle and 59%
in the third cycle (Scheme 1).
Scheme 1. Application of a Lewis Base Catalyst Immobilized
In summary, the novel and efficient nonmetallic catalyzed
regioselective ring-opening of aziridines with silylated nu-
cleophiles is described herein. The reaction provides a facile
route to the synthesis of â-amino acids and 1,2-diamines.
Further investigations of the scope of the reaction are
currently underway.
on Silica Gel to the Ring Opening and Its Reusability
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from the Japan Society
for the Promotion of Science.
procedures in cases where this catalyst is used prompted us
to investigate its application to the present reaction. When
aziridine 1a was treated with TMSCN in the presence of 40
mol % of 3-(dimethylamino)propyl-functionalized silica gel
in acetonitrile at 60 °C for 72 h, the desired ring opening
proceeded, affording 2a in 66% yield. The catalyst was found
to be reusable after washing with an alkaline solution and
Supporting Information Available: General experimen-
tal procedures and characterization for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL051186F
CDCl3) δ 0.84 (t, 3H, n-C5H10CH3, J ) 6.8 Hz), 1.07-1.60 (m, 10H,
n-C5H10CH3), 2.44 (s, 3H, Ar-CH3), 2.50-2.68 (m, 2H, CH2CN), 3.38-
3.46 (m, 1H, N-CH), 4.75 (d, 1H, NH, J ) 7.6 Hz, D2O exchangeable),
7.32 (d, 2H, m-H, J ) 8.2 Hz), 7.75 (d, 2H, o-H, J ) 8.2 Hz); 13C NMR
(CDCl3) δ ) 14.05, 21.60, 22.45, 25.13, 25.30, 28.50, 31.49, 33.90, 50.01,
116.74(CN), 126.96, 129.76, 136.93, 143.83; MS (CI, methane) m/z (relative
intensity) 309 ([M + 1]+, 61), 268 ([M - CH2CN]+, 100); HRMS (CI,
methane) m/z calcd for C16H25N2O2S (M + H) 309.1637, found 309.1646.
Anal. Calcd for C16H24N2O2S: C, 62.30; H, 7.84; N, 9.08. Found: C, 61.89;
H, 7.52; N, 8.92.
(14) Representative procedure for ring opening of an aziridine 1a. To a
solution of N-tosylaziridine 1a (84.3 mg, 0.3 mmol) in acetonitrile (1.2
mL) were added trimethylsilyl cyanide (48 µL, 0.36 mmol) and TMEDA
(9 µL, 0.06 mmol). The mixture was stirred at room temperature and the
progress of the reaction was monitored by TLC. After consumption of the
starting material, removal of solvent under reduced pressure gave the crude
product, which was purified by silica gel column chromatography using
n-hexane-AcOEt as an eluent to give the ring-opening product 2a (76.7
mg, 83%): colorless oil; IR (neat, cm-1) 2251 (CN); 1H NMR (270 MHz,
3512
Org. Lett., Vol. 7, No. 16, 2005