Cerium(III) chloride promoted highly regioselective ring opening of epoxides and aziridines using NaN3 in acetonitrile: A facile synthesis of 1,2-azidoalcohols and 1,2-azidoamines

Article abstract of DOI:10.1021/ol016979q

A convenient and efficient synthesis of 1,2-azidoalcohols and 1,2-azidoamines has been achieved by ring opening of epoxides and aziridines using cerium(III) chloride and sodium azide in acetonitrile. The reaction is highly regioselective and afforded the corresponding products in good to excellent yields under mild and neutral reaction conditions. The method is very rapid and equally compatible for both epoxides and aziridines.

Full text of DOI:10.1021/ol016979q

ORGANIC
LETTERS
2002
Vol. 4, No. 3
343-345
Cerium(III) Chloride Promoted Highly
Regioselective Ring Opening of
Epoxides and Aziridines Using NaN in
3
Acetonitrile: A Facile Synthesis of
1,2-Azidoalcohols and 1,2-Azidoamines†
Gowravaram Sabitha,* R. Satheesh Babu, M. Rajkumar, and J. S. Yadav
Organic DiVision I, Indian Institute of Chemical Technology,
Hyderabad 500 007, India
sabitha@iict.ap.nic.in
Received October 31, 2001 (Revised Manuscript Received December 20, 2001)
ABSTRACT
A convenient and efficient synthesis of 1,2-azidoalcohols and 1,2-azidoamines has been achieved by ring opening of epoxides and aziridines
using cerium(III) chloride and sodium azide in acetonitrile. The reaction is highly regioselective and afforded the corresponding products in
good to excellent yields under mild and neutral reaction conditions. The method is very rapid and equally compatible for both epoxides and
aziridines.
1,2-Azidoalcohols are versatile intermediates in organic
synthesis since they are very important precursors of â-amino
alcohols and vicinal diamines, which are present in numerous
natural products.1 Further, their importance is significant in
the chemistry of carbohydrates and nucleosides.2 1,2-
Azidoamines are compounds of synthetic interest because
of the reduced products, vicinal diamines which are biologi-
cally important compounds3 and have varied applications in
organic synthesis.4 Therefore, there is significant current
interest in the ring opening reactions of epoxides and
aziridines using azide as nucleophile. Azidohydrins and
azidoamines can be easily prepared from epoxides and
aziridines by the ring opening reaction. Because of their ring
strain and high reactivity, their reactions with various
nucleophiles lead to high regio- and stereoselective ring-
opened products.
Generally, azidohydrins are prepared through the ring
opening of epoxides by using different azides in suitable
solvents. Even though the classical protocol uses2a,b,5 sodium
azide and ammonium chloride, the azidolysis reaction
requires a long reaction time (12-48 h) and the azidohydrin
is often accompanied by isomerization, epimerization, and
rearrangement of products.6a The reagents for azidohydrin
† IICT Communication No. 01/X/13.
(1) (a) Horton, D.; Wander, J. D. The Carbohydrates; Pigman, W.,
Horton, D., Eds., Academic Press: New York, 1980; Vol. 1B, p 643. (b)
Schubert, J.; Schwesinger, R.; Prinzbach, H. Angew. Chem., Int. Ed. Engl.
1984, 23, 167.
(2) (a) The Chemistry of the Azido Group; Patai, S., Ed.; Wiley: New
York, 1971. (b) Scriven, E. F. V.; Turnbull, K. Chem. ReV. 1988, 88, 297.
(c) Coe, D. M.; Myers, P. L.; Parry, D. M.; Roberts, S. M.; Storer, R. J.
Chem. Soc., Chem. Commun. 1990, 151. (d) Jacobs, G. A.; Tino, J. A.;
Zahler, R. Tetrahedron Lett. 1989, 30, 6955.
(3) Reets, M. T.; Jaeger, R.; Drewlies, R.; Hubel, M. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 103 and references therein.
(4) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998,
37, 2850.
(5) (a) Crotti, P.; Di Bussolo, V.; Favero, L.; Macchia, F.; Pineschi, M.
Eur. J. Org. Chem. 1998, 5, 1675. (b) Nugent, T. C.; Hudlicky, T. J. Org.
Chem. 1998, 63, 510. (c) Swift, G.; Swern, D. J. Org. Chem. 1967, 32,
511. (d) Chini, M.; Crotti, P.; Macchia, F. Tetrahedron Lett. 1990, 31, 5641.
(6) (a) Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. J. Org. Chem.
1999, 64, 6094 and references therein. (b) Fringuelli, F.; Piermatti, O.; Pizzo,
F.; Vaccaro, L. J. Org. Chem. 2001, 66, 4719.
10.1021/ol016979q CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/05/2002

synthesis are the combined use of NaN3 or TMSN3 and a
Lewis acid or a transition metal complex7 or reaction in the
presence of tetrabutylammonium salt.8 Recently pH-con-
trolled azidolysis of epoxides was also studied in water using
various Lewis acids and NaN3.6 Similarly, 1,2-azidoamines
are also compounds of synthetic interest in organic synthesis,
because they are easily transformed to biologically important
vicinal diamines. These Vic azidoamines are generally
prepared by ring opening reaction of aziridines. Yeung and
co-workers reported the azidolysis of N-tosylaziridines with
TMSN3 in the presence of a chromium complex.9,10 However,
the results were not satisfactory regarding the yields and
regioselectivity (1:1) with aziridines derived from terminal
aliphatic compounds as well as styrene, and the reaction
times were also too long (2-9 days). Azidolysis of aziridines
was also reported with TMSN3 but it requires tetrabutyl-
ammoniumfluoride11 as a trigger. Another report describes
the ring opening of nonactivated aziridines with TMSN3
to yield the corresponding azidoamines.12 Very recently,
Lectka et al.13 reported the azidolysis of N-benzylaziridine
catalyzed by transition metal based complexes, which causes
rearrangement to oxazolines. Although all the above methods
and procedures have their own advantages, many of these
procedures suffer from one or more drawbacks such as longer
reaction times, strongly acidic conditions, unsatisfactory
yields, and lack of regioselectivity, cost, and stability of the
reagent. In this context, there is a great need to develop a
mild and efficient method, which can be a valuable alterna-
tive for the synthesis of 1,2-azidoalcohols and 1,2-azido-
amines.
sodium azide system in a mixture of acetonitrile and water
(9:1) (Schemes 1 and 2).
As a typical example, the reaction of phenyl glycidyl ether
(1 mmol, entry 1, Table 1) was tested with a mixture of
Table 1. Regioselective Ring Opening of Epoxides and
Aziridines Using CeCl3‚7H2O/NaN3
In the context of our recent report in the regioselective
ring opening of epoxides and aziridines14 and the water-
tolerant reagent15 cerium(III) chloride, which has been used
for several regio- and chemoselective transformations,16 we
herein disclose our results on regioselective azidolysis of
epoxides and aziridines using a cerium(III) chloride and
(7) (a) Birkofer, I.; Kaiser, W. Liebigs Ann. Chem. 1975, 266. (b) Blandy,
C.; Choukroun, R.; Gervais, D. Tetrahedron Lett. 1993, 24, 4189. (c) Caron,
M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1560. (d) Nugent, W. A. J.
Am. Chem. Soc. 1992, 114, 2768. (e) For a recent Review, see: Paterson,
I.; Berrisford, D. J. Organic Synthesis Highlights III; Mulzer, J., Waldmann,
H., Eds.; Wiley-VCH, 1998.
(8) Schneider, C. Synlett 2000, 12, 1840.
(9) Leung, W. H.; Yu, M. T.; Wu, M. C.; Yeung, L. L. Tetrahedron
Lett. 1996, 37, 891.
(10) For aziridine opening with TMSN3 catalyzed by a chiral chro-
mium(III) complex, see: Li, Z.; Fernandez, M.; Jacobson, E. N. Org. Lett.
1999, 1, 1611.
(11) Wu, J.; Hou, X. L.; Dai, L. X. J. Org. Chem. 2000, 65, 1344.
(12) Chandrasekhar, M.; Sekar, G.; Singh, V. K. Tetrahedron Lett. 2000,
41, 10079.
(13) Ferraris, D.; Drury, W. J., III; Cox, C.; Lectka, T. J. Org. Chem.
1998, 63, 4568.
(14) Sabitha, G.; Satheesh Babu, R.; Rajkumar, M.; Srinivas Reddy, Ch.;
Yadav, J. S. Tetrahedron Lett. 2001, 42, 3955.
1
a The products obtained were characterized by IR, H NMR, and mass
spectra. b Yield refers to the isolated pure products after column chroma-
tography; yields in parantheses corresponds to the other isomer.
(15) Imamoto, T. Lanthanides in Organic Synthesis; Academic Press:
New York, 1994.
CeCl3‚7H2O (0.5 mmol) and NaN3 (1 mmol) in an aceto-
nitrile and water mixture (9:1). After 3 h the complete
conversion was achieved at acetonitrile reflux temperature
to afford 1-azido-3-phenoxy-2-propanol in 99% yield. Be-
cause of the predominant attack of azide ion on the less
hindered carbon of the epoxide, all the terminal epoxides
gave highly regioselective azidohydrins in quantitative yields.
(16) (a) Sabitha, G.; Satheesh Babu, R.; Rajkumar, M.; Srividya, R.;
Yadav, J. S. Org. Lett. 2001, 3, 1149. (b) Ballini, R.; Marcantoni, E.;
Perrella, S. J. Org. Chem. 1999, 64, 2954. (c) Alessandrini, S.; Bartoli, G.;
Bellucci, M. C.; Dalpozzo, R.; Malavolta, M.; Marcantoni, E.; sambri, L.
J. Org. Chem. 1999, 64, 1986. (d) Liu, H.-J.; Shia, K.-S.; Shang, X.; Zhu,
B.-Y. Tetrahedron 1999, 55, 3803 and references therein. (e) Denmark, S.
E.; Nicaise, O. Synlett 1993, 359. (f) Di Deo, M.; Marcantoni, E.; Torregiani,
E.; Bartoli, G.; Bellucci, M. C.; Bosco, M.; Sambri, L. J. Org. Chem. 2000,
65, 2830.
344
Org. Lett., Vol. 4, No. 3, 2002

As expected in the case of styrene oxide (entry 5, Table 1),
2-azido-2-phenylethanol was obtained as the major product
due to the formation of the stabilized benzylic cation during
the reaction (Scheme 1). In the case of cyclic epoxides, the
Scheme 2
Scheme 1
in good yields (Scheme 2). As described in the case of ring
opening reactions of epoxides, high regioselectivity was
achieved in the case of terminal acyclic aziridines, affording
1- and 2- azido products with a ratio of >99:1 (entries 14
and 15, Table 1) because of the attack of nucleophile on the
less substituted aziridine carbon. In the case of cyclic
aziridine (entry 13, Table 1), the reactions were completely
anti stereoselective, affording trans azidoamines. As ex-
pected, the reaction of styrene N-tosylaziridine (entry 11,
Table 1) afforded the 1- and 2-azido products with a
selectivity of 97:3 due to attack at the benzylic carbon atom.
It is compulsory to use the acetonitrile and water mixture
(9:1) at acetonitrile reflux temperature for more than 2 h,
because as described in our earlier communication,14 in the
absence of water the chlorohydrins and chloroamines were
isolated as products. To determine the role of CeCl3, this
reaction was tested without use of cerium(III) chloride; the
reaction failed to give any product, but after prolonged
reaction time (12 h) ∼10% diol was isolated.
ring-opened products were completely anti-stereoselective,
giving only the trans isomers. Comparison experiments were
conducted for each epoxide classes (entries 1, 5, 7, and 10,
Table 1) using classical procedure (NH4Cl/NaN3 in CH3OH:
H2O 8:1) and the results are summarized in Table 2. This
Table 2. Comparative Study for Regioselective Ring Opening
of Epoxidesa
In conclusion, we have described a novel and regioselec-
tive ring opening of epoxides and aziridines with the CeCl3/
NaN3 system in an acetonitrile/water mixture (9:1) for the
synthesis of 1,2-azidoalcohols and 1,2-azidoamines under
mild and neutral reaction conditions. The advantages of the
present protocol, such as shorter reaction times, simplicity
in operation, the low cost of reagents, high yields of products,
and its equally compatible reaction procedure for both
epoxides and aziridines, make it a valuable alternative to
the existing reagents reported in the literature.
Acknowledgment. R.S.B. and M.R. thank CSIR, New
Delhi for the award of fellowships.
Supporting Information Available: Spectral data for all
compounds along with a detailed experimental procedure.
This material is available free of charge via the Internet at
http://pubs.acs.org.
a A: 0.5 equiv of CeCl3/1.1 equiv of NaN3, CH3CN:H2O (9:1), reflux.
B: 5 equiv of NH4Cl/2.2 equiv of NaN3, MeOH:H2O (8:1), reflux. Yield
refers to the isolated pure products after column chromatography; yields in
parantheses corresponds to the other isomer.
OL016979Q
indicates the superiority of our protocol in terms of regio-
selectivity, yields, and reaction times.
(17) General procedure: To a mixture of epoxide/aziridine (1 mmol)
and CeCl3.7H2O (0.5 mmol) in acetonitrile and water (9:1, 10 mL) was
added NaN3 (1.1 mmol), and the reaction mixture was stirred at acetonitrile
reflux temperature for a specified time as required to complete the reaction
(Table 1). After completion as indicated by TLC, the reaction mixture was
extracted with ethyl acetate, the combined organic layers were washed with
H2O and brine, dried over anhydrous Na2SO4, and evaporated under reduced
pressure. The residue was subjected to flash chromatography on silica gel
(eluent: hexane/ethyl acetate) to provide the pure azidohydrin/azidoamine.
Similarly, the ring opening of N-substituted aziridines
proceeded very smoothly with CeCl3‚7H2O (0.5 mmol) and
NaN3 (1 mmol) in an acetonitrile and water mixture (9:1).
Complete conversion was achieved in 3 h at acetonitrile
reflux temperature to afford the corresponding azidoamines
Org. Lett., Vol. 4, No. 3, 2002
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