Sc(OTf)3-Catalyzed [3+2]-cycloaddition of aziridines with nitriles under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2006.01.021

[3+2]-Cycloaddition of aziridines with various nitriles in the absence of organic solvent catalyzed by Sc(OTf)₃ afforded the corresponding imidazolines in good to excellent yields under extremely mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2006.01.021

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1509–1512
Sc(OTf)3-Catalyzed [3+2]-cycloaddition of aziridines
with nitriles under solvent-free conditions
a
a
Jie Wu,a,b, Xiaoyu Sun and Hong-Guang Xia
*
aDepartment of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
Received 2 December 2005; revised 28 December 2005; accepted 5 January 2006
Abstract—[3+2]-Cycloaddition of aziridines with various nitriles in the absence of organic solvent catalyzed by Sc(OTf)3 afforded
the corresponding imidazolines in good to excellent yields under extremely mild reaction conditions.
Ó 2006 Elsevier Ltd. All rights reserved.
The use of Lewis acids in organic synthesis, especially in
catalysis has been one of the most rapidly developing
fields in synthetic organic chemistry.1 Among them, lan-
thanide triflates have attracted much attentions in the
last decade due to their versatilities and water-stability.1
Aziridine is a versatile building block for the syntheses
of many nitrogen-containing biologically active mole-
cules.2 It reacts with various nucleophiles, and its ability
to undergo regioselective ring-opening contributes lar-
gely to its high synthetic value.2–6 In the course of our
ongoing studies on novel methods for the aziridine
ring-opening reactions, we were attracted to readily
available lanthanide triflates as catalysts for ring-open-
ing reactions of aziridines with carbon nucleophiles.
During our studies for the reaction of N-tosyl-2-phenyl-
aziridine with ethyl cyanoformate catalyzed by lantha-
nide triflates and other Lewis acids, we found that, the
initial attempts to effect this transformation led to a sur-
prising result when the reactions were performed in ace-
tonitrile. No desired product was detected, while [3+2]-
cycloaddition of N-tosyl-2-phenylaziridine with acetoni-
trile in the presence of lanthanide triflates occurred.
aziridines.7 Although most nitriles are known to be poor
dipolarophiles for intermolecular [3+2]-cycloaddition
reactions,8 utilization of nitriles as dipolarophiles for
[3+2]-cycloaddition with aziridines9,10 is promising since
imidazoline would be generated during the process. It is
well-known that imidazolines exhibit a wide range of
pharmacological activities, such as anti-hyperglycemic,
anti-inflammatory, antinociceptive, immunomodulat-
ing, anti-oxidant, antitumor, and anti-cancer activi-
ties.11,12 However, the methods developed9,10 usually
suffered from harsh reaction conditions, stoichiometric
amounts of Lewis acids promoter, low yields, and side
reactions. For example, stoichiometric amounts of
BF3ÆEt2O10a,b or ZnX210c have to be utilized as promoter
for the [3+2]-cycloaddition of aziridines with nitriles in
order to achieve the respectable yields. However, only
low to moderate yields could be obtained. And also,
these Lewis acids employed are moisture sensitive.
Moreover, under these conditions the side reactions
are inevitable since halide anion from the promoter
would act as a nucleophile to attack the aziridine ring.
These drawbacks have prompted us to develop a simple,
efficient, and catalytic protocol for synthesis of imidazo-
lines utilizing [3+2]-cycloaddition of aziridines with nitr-
iles based on the observations above. We now disclose
our efforts on this area, which represent the first cata-
lytic protocol for synthesis of imidazolines utilizing
Sc(OTf)3 as catalyst in the [3+2]-cycloaddition of aziri-
dines with nitriles.
The cycloaddition reaction of aziridine with dipolaro-
philes, in particular, is a useful method for the syntheses
of nitrogen-containing five- and six-ring molecules.7,9,10
In most cases of this area, alkenes, and alkynes were in-
volved as dipolarophiles for the [3+2]-cycloaddition of
*
Initial studies were aimed at finding the optimal reaction
conditions for this [3+2]-cycloaddition reactions. Our
Corresponding author. Tel.: +86 2155 664619; fax: +86 2165
102412; e-mail: jie_wu@fudan.edu.cn
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.021

1510
J. Wu et al. / Tetrahedron Letters 47 (2006) 1509–1512
Table 1. Reaction of N-tosylaziridine 1 with nitrile 2 catalyzed by
Sc(OTf)3
Table 2. Reaction of N-tosylaziridine 1 with nitrile 2 catalyzed by
Sc(OTf)3 under solvent-free condition at air atmospherea,14
Me
R
Ts
Ts
N
Lewis acid (10 mol%)
Sc(OTf)3 (25 mol%)
solvent-free, r.t., air
Ts
Ts
N
N
N
N
N
+
MeCN
+
RCN
5.0 equiv.
2
Ar
Ph
CH2Cl2, r.t.
Ph
Ar
1a
2a
3a
1
3
Entry
Lewis acid
Yield (%)a
Entry Aziridine
Nitrile
2
Time Product Yield
1
(min)
3
(%)b
1
2
3
4
5
6
Sc(OTf)3
Yb(OTf)3
Dy(OTf)3
AgOTf
Zn(OTf)2
In(OTf)3
61
11
11
15
34
51
NTs
1
MeCN 2a
20
3a
73
R
R = H: 1a
a Isolated yield based on aziridine 1a.
2
3
4
1a
nPrCN 2b
PhCN 2c
BnCN 2d
25
20
25
3b
3c
3d
84
90
83
1a
1a
investigation began with the reaction of N-tosyl-2-
phenylaziridine 1a and acetonitrile 2a (1.2 equiv) in
dichloromethane catalyzed by lanthanide triflates and
other Lewis acids (10 mol %) (Table 1). Among the
Lewis acids (Sc(OTf)3, Yb(OTf)3, Dy(OTf)3, AgOTf,
Zn(OTf)2, In(OTf)3) were screened, Sc(OTf)3 was dem-
onstrated as the best catalyst (61% yield, Table 1, entry
1). Further studies established showed that the reaction
worked most efficiently in the absence of organic
solvents (considering the ease of operation, 5 equiv of
MeCN was used) among solvents investigation after
12 h. Reducing the amount of catalyst retarded the reac-
tion. However, to our delight, the reaction went to com-
pletion in 20 min with 73% isolated yield when the
amount of catalyst was increased to 25 mol %. No
improvement was observed when the usage of catalyst
kept increasing. Moreover, it is noteworthy that this
reaction could be run under the air without loss of
efficiency.
F3C
CN
5
6
7
1a
1a
1a
20
15
15
3e
3f
53
51
76
2e
F
CN
2f
F
CN
3g
2g
8
9
R = 4-Cl: 1b 2a
20
15
25
15
15
15
15
10
20
12
20
3h
3i
94
79
70
67
66
56
87
70
77
68
67
1b
1b
1b
1b
1b
2b
2c
2d
2f
10
11
12
13
14
15
16
17
18
3j
3k
3l
2g
3m
3n
3o
3p
3q
3r
R = 4-Me: 1c 2a
To demonstrate the generality of this method, we next
investigated the scope of this reaction under the opti-
mized conditions (in the absence of organic solvents,
25 mol % of Sc(OTf)3, air, rt) and the results are summa-
rized in Table 2. The operation was simple: nitrile
(5.0 equiv) was added to a mixture of aziridine 1
(0.25 mmol) and Sc(OTf)3 (25 mol %). The reaction mix-
ture was stirred at room temperature for a period of
time indicated in Table 2 under air atmosphere. After
the reaction was completed monitored by TLC, the mix-
ture was added to 5 mL of ethyl acetate, washed with
saturated aqueous NaHCO3, and extracted with ethyl
acetate. The organic extracts were dried (MgSO4),
filtered, and concentrated under reduced pressure.
Purification by column chromatography on silica gel
afforded the corresponding product. As shown in Table
2, this method was equally effective for both N-tosyl-
2-arylaziridines 1 and nitriles 2. Various substituted N-
tosyl-2-arylaziridines 1a–d reacted smoothly with
nitriles 2 to produce a range of imidazoline derivatives.
Complete conversion and good to excellent isolated
yields were observed for most of the substrates
employed. However, when other aziridines, such as 7-
tosyl-7-aza-bicyclo[4.1.0]heptane or N-tosyl-2-butylaziri-
dine, reacted with nitriles, the starting materials could
1c
1c
1c
1c
2b
2c
2d
2f
Ts
N
19
2a
30
3s
54
1d
20
1d
2c
120
3t
62
a Reaction conditions: aziridine (0.25 mmol), nitrile (5.0 equiv),
Sc(OTf)3 (25 mol %), room temperature.
b Isolated yield based on aziridine 1.
not be consumed even after 24 h and side products were
observed (results not shown in Table 2).
The possible mechanism for formation of the cycloaddi-
tion product was rationalized in Scheme 1, where the
aziridine nitrogen was coordinated to Sc(OTf)3 generat-
ing a highly reactive intermediate 4, which would then
undergo a [3+2]-cycloaddition reaction with nitriles to
provide the substituted imidazoline 3. To support the
mechanism, the ring-opening reaction of a chiral aziri-

J. Wu et al. / Tetrahedron Letters 47 (2006) 1509–1512
1511
R
C
2
N
R
N
Ts
C
Ts
N
Sc(OTf)3
N
Sc(OTf)3
Ts
N
Sc(OTf)3
Ar
Ar
Ar
1
4
5
R
R
C
N
N
Sc(OTf)3
Ts
N Ts
N
Ar
Ar
3
6
Scheme 1.
dine, R-(À)-1a (>90 ee),13 with acetonitrile was carried
out under the same conditions shown in Table 1 and
nonracemic imidazoline was produced ([a]20 À10.2 (c
0.38, CHCl3)). Based on this observation, it was clear
that the reaction proceeded through a cationic interme-
diate 4 (Scheme 1) instead of a stable benzylic carbocat-
ion intermediate 6 from which a racemic product could
be expected.
247; (l) Dhanukar, V. H.; Zavialov, L. A. Curr. Opin. Drug
Discovery Dev. 2002, 5, 918.
3. For examples of the reaction of aziridine with alcohols or
phenols see: (a) Bodenan, J.; Chanet-Ray, J.; Vessiere, R.
Synthesis 1992, 288; (b) Bellos, K.; Stamm, H. J. Org.
Chem. 1995, 60, 5661; (c) Wipf, P.; Uto, Y. Tetrahedron
Lett. 1999, 40, 5165; (d) Stamm, H.; Schneider, L. Chem.
Ber. 1974, 107, 2870; (e) Hou, X.-L.; Fan, R.-H.; Dai,
L.-X. J. Org. Chem. 2002, 67, 5295; (f) Fan, R.-H.; Hou,
X.-L. J. Org. Chem. 2003, 68, 726.
In conclusion, we described Sc(OTf)3 as a novel and effi-
cient sub-catalyst in the [3+2]-cycloaddition of aziri-
dines with nitriles under extremely mild reaction
conditions, which provided a convenient way for the
synthesis of imidazolines. The advantages of this meth-
od include: (1) employing easily available, water-stable
Sc(OTf)3 as sub-catalyst; (2) experimentally operational
ease; (3) extremely mild conditions—room temperature
under air atmosphere; and (4) in the absence of organic
solvents.
4. For examples of the reaction of aziridine with thiols see:
(a) Antolini, L.; Bucciarelli, M.; Caselli, E.; Davoli, P.;
Forni, A.; Moretti, I.; Prati, F.; Torre, G. J. Org. Chem.
1997, 62, 8784; (b) Maligres, P. E.; See, M. M.; Askin, D.;
Reider, P. J. Tetrahedron Lett. 1997, 38, 5253; (c) Bae, J.
H.; Shin, S. H.; Park, C. S.; Lee, W. K. Tetrahedron 1999,
55, 10041; (d) Katagiri, T.; Takahashi, M.; Fujiwara, Y.;
Ihara, H.; Uneyama, K. J. Org. Chem. 1999, 64, 7323; (e)
Wu, J.; Hou, X.-L.; Dai, L.-X. J. Chem. Soc., Perkin
Trans. 1 2001, 1314; (f) Hou, X.-L.; Fan, R.-H.; Dai, L.-X.
J. Org. Chem. 2002, 67, 5295; (g) Fan, R.-H.; Hou, X.-L.
J. Org. Chem. 2003, 68, 726; (h) Wu, J.; Sun, X.; Li, Y.
Eur. J. Org. Chem. 2005, 4271.
5. For examples of the reaction of aziridine with amines see:
(a) Nakajima, K.; Tanaka, T.; Morita, K.; Okawa, K.
Bull. Chem. Soc. Jpn. 1980, 53, 283; (b) Meguro, M.;
Yamamoto, Y. Heterocycles 1996, 43, 2473; (c) Lucet, D.;
Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998,
37, 2580; (d) Sekar, G.; Singh, V. K. J. Org. Chem. 1999,
64, 2537; (e) Hou, X.-L.; Fan, R.-H.; Dai, L.-X. J. Org.
Chem. 2002, 67, 5295; (f) Fan, R.-H.; Hou, X.-L. J. Org.
Chem. 2003, 68, 726; (g) Wu, J.; Sun, X.; Li, Y. Eur. J.
Org. Chem. 2005, 4271.
Acknowledgments
Financial support from National Natural Science Foun-
dation of China (20502004), Ministry of Education of
China, and the Science and Technology Commission
of Shanghai Municipality is gratefully acknowledged.
References and notes
6. For examples of the reaction of aziridine with silyl
nucleophiles, see: (a) Matsubara, S.; Kodama, T.; Uti-
moto, K. Tetrahedron Lett. 1990, 31, 6379; (b) Leung, W.
H.; Yu, M. T.; Wu, M. C.; Yeung, L. L. Tetrahedron Lett.
1996, 37, 891; (c) Ferraris, D.; Drury, W. J., III; Cox, C.;
Lectka, J. J. Org. Chem. 1998, 63, 4568; (d) Li, Z.;
Fernandez, M.; Jacobsen, E. N. Org. Lett. 1999, 1, 1611;
(e) Chandrasekhar, M.; Sekar, G.; Singh, V. K. Tetra-
hedron Lett. 1990, 31, 6379; (f) Shin, S.-H.; Han, E. Y.;
Park, C. S.; Lee, W. K.; Ha, H.-J. Tetrahedron: Asymme-
try 2000, 11, 3293; (g) Yadav, J. S.; Reddy, B. V. S.;
Kumar, G. M.; Murthy, C. V. S. R. Synth. Commun. 2000,
32, 1797; (h) Reddy, M. A.; Reddy, L. R.; Bhanumathi,
N.; Rao, K. R. Chem. Lett. 2001, 246; (i) Osborn, H. M.
I.; Sweeney, J. B. Synlett 1994, 145; (j) Chandrasekhar,
M.; Sekar, G.; Singh, V. K. Tetrahedron Lett. 2000, 41,
10079; (k) Wu, J.; Hou, X.-L.; Dai, L.-X. J. Org. Chem.
2000, 65, 1344; (l) Minakata, S.; Okada, Y.; Oderaotoshi,
1. Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.;
Wiley-VCH Verlag GmbH: Germany, 2000.
2. For reviews of syntheses and reactions of activated and
unactivated aziridines see: (a) Pawda, A.; Pearson, W. H.;
Lian, B. W.; Bergmeier, S. C. In Comprehensive Hetero-
cyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven,
E. F. V., Eds.; Pergamon: New York, 1996; Vol 1a; (b)
Pawda, A.; Woolhouse, A. D. In Comprehensive Hetero-
cyclic Chemistry; Lwowski, W., Ed.; Pergamon: Oxford,
UK, 1984; Vol. 7; (c) Tanner, D. Angew. Chem., Int. Ed.
1994, 33, 599; (d) Ibuka, T. Chem. Soc. Rev. 1998, 27, 145;
(e) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev.
1997, 97, 2341; (f) Stamm, H. J. Prakt. Chem. 1999, 319;
(g) Hu, X. E. Tetrahedron 2004, 60, 2701; (h) Ma, L. G.;
Xu, J. X. Prog. Chem. 2004, 16, 220; (i) Rayner, C. M.
Synlett 1997, 11; (j) McCoull, W.; Davis, F. A. Synthesis
2000, 1347; (k) Sweeney, J. B. Chem. Soc. Rev. 2002, 31,

1512
J. Wu et al. / Tetrahedron Letters 47 (2006) 1509–1512
Y.; Komatsu, M. Org. Lett. 2005, 7, 3509; (m) Wu, J.;
Sun, X.; Xia, H.-G. Eur. J. Org. Chem. 2005, 4769.
B.; Renard, P.; Guardiola-Lamaitre, B.; Manechez, D.;
Penicaud, L.; Ktorza, A.; Godfroid, J.-J. J. Med. Chem.
1999, 42, 1587.
7. (a) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley: Chichester, UK, 1984; Vol. 2, p 89;
(b) Ungureanu, I.; Klotz, P.; Mann, A. Angew. Chem., Int.
Ed. 2000, 39, 4615; (c) Pohlhaus, P. D.; Bowman, R. K.;
Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 2294; (d)
Carruthers, W. Cycloaddition in Organic Synthesis; Perg-
amon: Oxford, 1990; p 1; (e) Takano, S.; Iwabuchi, Y.;
Ogasawara, K. J. Am. Chem. Soc. 1987, 109, 5523; (f)
DeShong, P.; Kell, D. A.; Sidler, D. R. J. Org. Chem.
1985, 50, 2309; (g) Metra, P.; Hamelin, J. J. Chem. Soc.,
Chem. Commun. 1980, 1038; (h) Gaebert, C.; Siegner, C.;
Mattay, J.; Toubartz, M.; Steenken, S. J. Chem. Soc.,
Perkin Trans. 2 1998, 2735; (i) Domingo, L. R. J. Org.
Chem. 1999, 64, 3922; (j) Iwamoto, K.; Kojima, M.;
Chatani, N.; Murai, S. J. Org. Chem. 2001, 66, 166; (k)
Masahiro, T.; Youichi, N.; Keiichiro, F. Heterocycles
1994, 39, 39; (l) Luigi, C.; Franco, B.; Piero, L. P.
Synthesis 1994, 287; (m) Gaebert, C.; Mattay, J. Tetrahe-
dron 1997, 53, 14297; (n) Sisko, J.; Weinerb, S. M. J. Org.
Chem. 1991, 56, 3210; (o) Bergmeier, S. C.; Fundy, S. L.;
Seth, P. P. Tetrahedron 1999, 55, 8025; (p) Sugita, Y.;
Kimura, Y.; Yokoe, I. Tetrahedron Lett. 1999, 40,
5877; (q) Nakagawa, M.; Kawahara, M. Org. Lett. 2000,
2, 953.
8. For reaction of activated nitriles with azides, see: (a)
Demko, Z. P.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2113; (b) Demko, Z. P.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 2110.
9. (a) Hiyama, T.; Koide, H.; Fujita, S.; Nozaki, H.
Tetrahedron 1973, 29, 3137; (b) Legters, J.; Willems, J.
G. H.; Thijs, L.; Zwanenburg, B. Recl. Trav. Chim. Pays-
Bas 1992, 111, 59.
10. (a) Papa, C.; Tomasini, C. Eur. J. Org. Chem. 2000, 1569;
(b) Prasad, B. A. B.; Pandey, G.; Singh, V. K. Tetrahedron
Lett. 2004, 45, 1137; (c) Ghorai, M. K.; Das, K.; Kumar,
A.; Ghosh, K. Tetrahedron Lett. 2005, 46, 4103.
11. Bihan, G. L.; Rondu, F.; Tounian, A. P.; Wang, X.; Lidy,
S.; Touboul, E.; Lamouri, A.; Dive, G.; Huet, J.; Pfeiffer,
12. (a) Gilman, A. G.; Goodman, L. S. In The Pharmacolog-
ical Basis of Therapeutics, 10th ed.; Macmillan: New York,
2001, Chapter 10; pp 215–268; (b) Greenhill, J. V.; Lue, P.
Prog. Med. Chem. 1993, 30, 203.
13. (a) Alonso, D. A.; Andersson, P. G. J. Org. Chem. 1998,
63, 9455; (b) Berry, M. B.; Craig, D. Synlett 1992, 41.
14. General procedure: Nitrile (5.0 equiv) was added to a
mixture of aziridine
1 (0.25 mmol) and Sc(OTf)3
(25 mol %). The reaction mixture was stirred at room
temperature for a period of time indicated in Table 1
under air atmosphere. After the reaction was completed
monitored by TLC, the mixture was added to 5 mL of
ethyl acetate, washed with saturated aqueous NaHCO3,
and extracted with ethyl acetate. The organic extracts were
dried (MgSO4), filtered, and concentrated under reduced
pressure. Purification by column chromatography column
on silica gel afforded the corresponding product. Selected
examples: 2-Methyl-4-phenyl-1-tosyl-4,5-dihydro-1H-imid-
azole 3a:10 1H NMR (400 MHz, CDCl3): d 2.40 (s, 3H),
2.46 (s, 3H), 3.64 (t, J = 11.2 Hz, 1H), 4.17 (t, J = 10 Hz,
1H), 4.98 (t, J = 9.8 Hz, 1H), 6.98–7.05 (m, 2H), 7.25–7.27
(m, 3H), 7.35 (d, J = 8.32 Hz, 2H), 7.75 (d, J = 8.32 Hz,
2H). 4-Phenyl-2-propyl-1-tosyl-4,5-dihydro-1H-imidazole
3b:10 1H NMR (400 MHz, CDCl3): d 1.00–1.04 (m, 3H),
1.79–1.80 (m, 2H), 2.43 (s, 3H), 2.72–2.73 (m, 2H), 3.60 (t,
J = 9.8 Hz), 4.14 (t, J = 9.8, 1H), 4.96–5.00 (m, 1H), 7.02–
7.03 (m, 2H), 7.23–7.30 (m, 3H), 7.33 (d, J = 8.32 Hz, 2H),
7.73 (d, J = 8.32 Hz, 2H). 2,4-Diphenyl-1-tosyl-4,5-di-
hydro-1H-imidazole 3c:10 1H NMR (400 MHz, CDCl3): d
2.43 (s, 3H), 3.86 (dd, J = 11.2, 8.0 Hz, 1H), 4.44 (t,
J = 9.8 Hz, 1H), 4.99 (t, J = 9.8 Hz, 1H), 6.97–6.98 (m,
2H), 7.20–7.22 (m, 5H), 7.39–7.41 (m, 4H), 7.51–7.56 (m,
1H), 7.77 (d, J = 8.4 Hz, 2H). 2-Benzyl-4-phenyl-1-tosyl-
4,5-dihydro-1H-imidazole 3d:10 1H NMR (400 MHz,
CDCl3): d 2.43 (s, 3H), 3.59 (t, J = 8.0 Hz, 1H), 4.13–
4.18 (m, 3H), 5.01–5.06 (m, 1H), 6.97–7.01 (m, 2H), 7.19–
7.40 (m, 12H).