Savoia et al.
SCHEME 1. Ring-Opening of the Aziridine 1 by Attack of
Heteronucleophiles
to be effective catalysts in the same solvent mixture either at
room temperature or at the reflux temperature.
In both cases, we obtained good results. As a matter of fact,
the benzylic azide 2b was formed exclusively and isolated in
high yield. A slightly lower yield of 2b was obtained using
sodium azide (2 equiv) and aluminum trichloride11 (10 mol %)
in 1:1 EtOH-H2O after 24 h at 25 °C. On the other hand,
trimethylsilyl azide,12 when used in aprotic solvents
(THF, CH2Cl2), gave a mixture of the azides 2b (prevalent) and
3b. The reaction rate increased in the presence of tetrabuty-
lammonium fluoride;12c,d in this case, the amount of the benzylic
amine 3b was also increased, such that this compound could
be isolated by column chromatography.
The reactions with the primary amines benzylamine and
p-anisidine in different conditions always gave mixtures of the
isomeric products 2c,d and 3c,d. The best ratio in favor of 2c
(75:25) and 3d (71:29) was obtained in the presence of the
hydrated ceric salt in acetonitrile-water. In comparison, the use
of anhydrous zinc triflate13 or lithium perchlorate13,14 in aceto-
nitrile led to lower selectivities. Moreover, no reaction was
observed with benzylamine and zinc triflate in dichloromethane.
All the four compounds 2c,d and 3c,d could be isolated,
preferably from the properly enriched reaction mixtures. Simi-
larly, the reaction with dibenzylamine in the optimal reaction
conditions gave the two products 2e and 3e in an almost 1:1
ratio, and they were separated chromatographically with some
difficulty.
to define the optimal reaction conditions allowing for a selective
ring-opening.
Results and Discussion
The positive effect of both the protic solvent and the cerium
salt was particularly evident in the reactions of the aziridine 1
with aromatic thiols. In the case of 2-naphthalenethiol (1.1
equiv), the benzylic sulfide 2f was obtained exclusively with
high yield after heating in the presence of the hydrated cerium
salt in 9:1 acetonitrile-H2O at the reflux temperature for 2 h.15
On the other hand, lower reaction rates and mixtures of 2f and
3f were observed in the absence of the catalyst in the same
solvent mixture and in dichloromethane.16 Similar results were
obtained in the case of thiophenol, whereas the reaction with
benzylthiol gave a mixture of the products 2h and 3h (70:30)
in the optimized conditions. The reaction with n-butylthiol was
even less satisfactory, as it afforded a mixture, from which only
the prevalent sulfide 2i and the alcohol 2a were isolated by
column chromatography. Finally, t-butylthiol was ineffective,
as we only obtained the alcohols 2a and 3a, coming from the
competitive ring opening by water.
The protocols for the Lewis acid promoted nucleophilic ring-
opening of analogous substituted aziridines, as described by
other groups, were taken into account. A series of reactions with
several heteronucleophiles in different experimental conditions
demonstrated that it is possible to activate the aziridine ring
and control the regioselectivity of the ring-opening process by
the proper choice of the reagent, Lewis acid, and solvent. The
reactions gave the products 2, coming from nucleophilic attack
at the more substituted aziridine carbon, either exclusively or
together with the alternative product 3 (Table 1). Initial attempts
involved water as the nucleophile in the presence of a protic8
or Lewis acid catalyst.9 Heating a mixture of aziridine 1 and
p-toluenesulfonic acid (20 mol %) in 9:1 acetonitrile-water at
the reflux temperature for 6 h gave a mixture of the regioiso-
meric ring-opening products 2a and 3a (82:18), which were
separated by column chromatography. Slightly better results
were obtained using cerium trichloride heptahydrate (30 mol
%) with other experimental conditions remaining constant; by
this manner, an improved regioselectivity (86:14) was obtained.
(11) Yongeun, K.; Hyun-Joon, H.; Kyusung, H.; Seung, W. K.; Hoseop,
Y.; Hyo, J. Y.; Min, S. K.; Won, K. L. Tetrahedron Lett. 2005, 46, 4407-
4409.
(12) TMSN3 cleaved N-tosyl and N-alkyl aziridines in polar aprotic
solvents: (a) Wu, J.; Sun, X.; Xia, H.-G. Eur. J. Org. Chem. 2005, 4769-
4772. (b) Minakata, S.; Okada, Y.; Oderaotoshi, Y.; Komatsu, M. Org.
Lett. 2005, 7, 3509-3512. (c) Wu, J.; Hou, X.-L.; Dai, L.-X. J. Org. Chem.
2000, 65, 1344-1348. (d) Xu, Q.; Appella, D. H. J. Org. Chem. 2006, 71,
8655-8657.
Then, efforts were devoted to optimizing the reaction with
sodium azide, with the aim of preparing the benzylic azide 2b.
By using sodium azide as the nucleophile source, an acetoni-
trile-water mixture (9:1) was used as the solvent. Having
observed no reactivity at the reflux temperature in the absence
of a Lewis acid, we evaluated ceric ammonium nitrate (CAN)9
and cerium trichloride heptahydrate,10 which were both found
(13) Bisai, A.; Prasad, B.; Singh, V. K. Tetrahedron Lett. 2005, 46,
7935-7939.
(14) N-Activated aziridines were cleaved by primary amines in the
presence of lithium perchlorate: (a) Yadav, J. S.; Reddy, B. V. S.;
Jyothirmai, B.; Murty, M. S. R. Synlett 2002, 53-56. (b) Thierry, J.;
Servajean, V. Tetrahedron Lett. 2004, 45, 821-823.
(15) Similarly, 1,2-disubstituted aziridines in the presence of boron
trifluoride underwent selective opening by attack of thiols at the substituted
aziridine carbon: Concellon, J. M.; Bernad, P. L.; Sua´rez, J. R. J. Org.
Chem. 2005, 70, 9411-9416.
(16) 1,2-Dialkylaziridines were cleaved by thiols in dichloromethane by
attack at the unsubstituted aziridine carbon: Bae, J. H.; Shin, S.-H.; Park,
C. S.; Lee, W. K. Tetrahedron 1999, 55, 10041-10046.
(8) Crousse, B.; Narizuka, S.; Bonnet-Delpon, D.; Be´gue´, J.-P. Synlett
2001, 679-681.
(9) Ring-opening of N-tosyl aziridines by water in the presence of cerium
ammonium nitrate has been reported: Chandrasekhar, S.; Narsihmulu, Ch.;
Shameem Sultana, S. Tetrahedron Lett. 2002, 43, 7361-7363.
(10) N-Tosyl aziridines were cleaved by sodium azide in the same
conditions: Sabitha, G.; Babu, R. S.; Rajkumar, M.; Yadav, J. S. Org. Lett.
2002, 4, 343-345.
3860 J. Org. Chem., Vol. 72, No. 10, 2007