F a cile Syn th eses of Oxa zolin es a n d Th ia zolin es w ith
N-Acylben zotr ia zoles u n d er Micr ow a ve Ir r a d ia tion
Alan R. Katritzky,* Chunming Cai, Kazuyuki Suzuki, and Sandeep K. Singh
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
Received October 13, 2003
Microwave reactions of 2-amino-2-methyl-1-propanol (2) or 2-aminoethanethiol hydrochloride (4)
with readily available N-acylbenzotriazoles 1a -j in the presence of SOCl2 produced 2-substituted
2-oxazolines 3a -j in 84-98% yields and 2-substituted thiazolines 5a -i in 85-97% yields,
respectively. With use of this method chiral oxazoline 6, bisoxazoline 7, bisthiazoline 8, and 5,6-
dihydro-4H-1,3-oxazines 9 or 10 have also been prepared in 82-96% yields. These results
demonstrate a new application of N-acylbenzotriazoles in the preparation of oxazolines and
thiazolines under mild conditions and short reaction times with microwave irradiation.
In tr od u ction
methods including imidate hydrochlorides,6g ortho esters,6h
imino ether hydrochlorides,6i aldehydes,6j or nitriles.6k-m
Thiazolines have been prepared (i) by the condensation
of amino thiols with nitriles,5a esters,7a imino ethers7b or
imino triflates,7c (ii) from N-acyl-2-aminoethanols6a,7d or
â-hydroxy thioamides,7e-g or (iii) by multistep conversions
from oxazolines.7h
However, there are limitations associated with these
literature methods: direct conversions of carboxylic acids
into the corresponding 2-oxazolines proceed with elimi-
nation of water at high temperatures (160-220 °C),
require long reaction times (12-18 h), and frequently give
low yields.1a,8 Use of nitriles requires a Lewis acid and
proceeds at high temperatures with elimination of
ammonia.6k Other methods utilize complex reagents6c,7f,g
or strongly acidic conditions.6f The problem of long
reaction times in the synthesis of oxazolines has been
solved to some extent by using microwaves,6e,i,m but the
reported procedures that involve domestic ovens suffer
from low reproducibility and lack general applicability.
Oxazolines and thiazolines are important hetero-
cycles.1,2 2-Oxazolines are structural entities in naturally
occurring iron chelators,3a,b cytotoxic cyclic peptides,3c,d
and antimitotic3e and neuroprotective agents.3f Well-
known applications of 2-oxazolines include their use as
synthetic intermediates,4a,b protecting groups,4c and chiral
auxiliaries.4d,e Thiazoline derivatives possess anti HIV-
1,5a antimitotic,5b and bioluminescent activities,5c and
have recently found applications as building blocks in
pharmaceutical drug discovery.5d-f
Reaction of carboxylic acids with amino alcohols is the
most common method for the synthesis of oxazolines.6a-f
Other carboxylate functionalities can be used in similar
(1) Frump, J . A. Chem. Rev. 1971, 71, 483.
(2) Fustero, S.; Salavert, E.; Navarro, A.; Mojarrad, F.; Fuentes, A.
S. Targets Heterocycl. Syst. 2001, 5, 235; Chem. Abstr. 2001, 138,
221480.
(3) (a) Peterson, T.; Falk, K.-E.; Leong, S. A.; Klein, M. P.; Neilands,
J . B. J . Am. Chem. Soc. 1980, 102, 7715. (b) Genet, J .-P.; Thorimbert,
S.; Touzin, A.-M. Tetrahedron Lett. 1993, 34, 1159. (c) Hamada, Y.;
Kato, S.; Shioiri, T. Tetrahedron Lett. 1985, 26, 3223. (d) Wipf, P.;
Miller, C. P. J . Am. Chem. Soc. 1992, 114, 10975. (e) Li, Q.; Woods, K.
W.; Claiborne, A.; Gwaltney, S. L., II; Barr, K. J .; Liu, G.; Gehrke, L.;
Credo, R. B.; Hui, Y. H.; Lee, J .; Warner, R. B.; Kovar, P.; Nukkala,
M. A.; Zielinski, N. A.; Tahir, S. K.; Fitzgerald, M.; Kim, K. H.; Marsh,
K.; Frost, D.; Ng, S.-C.; Rosenberg, S.; Sham, H. L. Bioorg. Med. Chem.
Lett. 2002, 12, 465. (f) Campiani, G.; de Angelis, M.; Armaroli, S.;
Fattorusso, C.; Catalanotti, B.; Ramunno, A.; Nacci, V.; Novellino, E.;
Grewer, C.; Ionescu, D.; Rauen, T.; Griffiths, R.; Sinclair, C.; Fumagalli,
E.; Mennini, T. J . Med. Chem. 2001, 44, 2507.
(4) (a) Meyers, A. I.; Mihelich, E. D. Angew. Chem., Int. Ed. Engl.
1976, 270. (b) Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837.
(c) Meyers, A. I.; Temple, D. L.; Haidukewych, D.; Mihelich, E. D. J .
Org. Chem. 1974, 39, 2787. (d) Meyers, A. I. Acc. Chem. Res. 1978, 11,
375. (e) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297.
(5) (a) Boyce, R. J .; Mulqueen, G. C.; Pattenden, G. Tetrahedron Lett.
1994, 35, 5705. (b) White, J . D.; Kim, T.-S.; Nambu, M. J . Am. Chem.
Soc. 1995, 117, 5612. (c) Toya, Y.; Takagi, M.; Kondo, T.; Nakata, H.;
Isobe, M.; Goto, T. Bull. Chem. Soc. J pn. 1992, 65, 2604. (d) Einsiedel,
J .; Hu¨bner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett. 2001, 11, 2533.
(e) Zarantonello, P.; Leslie, C. P.; Ferritto, R.; Kazmierski, W. M.
Bioorg. Med. Chem. Lett. 2002, 12, 561. (f) Wipf, P.; Reeves, J . T.;
Balachandran, R.; Day, B. W. J . Med. Chem. 2002, 45, 1901.
(6) (a) Wenker, H. J . Am. Chem. Soc. 1935, 57, 9. (b) Vorbru¨ggen,
H.; Krolikiewicz, K. Tetrahedron Lett. 1981, 22, 4471. (c) Vorbru¨ggen,
H.; Krolikiewicz, K. Tetrahedron Lett. 1993, 49, 9353. (d) Cwik, A.;
Hell, Z.; Hegedu¨s, A.; Finta, Z.; Horva´th, Z. Tetrahedron Lett. 2002,
43, 3985. (e) Marrero-Terrero, A. L.; Loupy, A. Synlett 1996, 245. (f)
Bandgar, B. P.; Pandit, S. S. Tetrahedron Lett. 2003, 44, 2331. (g)
Meyers, A. I.; Slade, J . J . Org. Chem. 1980, 45, 2785. (h) Kamata, K.;
Agata, I.; Meyers, A. I. J . Org. Chem. 1998, 63, 3113. (i) Oussaid, B.;
Berlan, J .; Soufiaoui, M.; Garrigues, B. Synth. Commun. 1995, 25, 659.
(j) Badiang, J . G.; Aube, J . J . Org. Chem. 1996, 61, 2484. (k) Bolm, C.;
Weickhardt, K.; Zehnder, M.; Ranff, T. Chem. Ber. 1991, 124, 1173. (l)
Clarke, D. S.; Wood, R. Synth. Commun. 1996, 26, 1335. (m) J nanesh-
wara, G. K.; Deshpande, V. H.; Lalithambika, M.; Ravindranathan,
T.; Bedekar, A. V. Tetrahedron Lett. 1998, 39, 459.
(7) (a) Busacca, C. A.; Dong, Y.; Spinelli, E. M. Tetrahedron Lett.
1996, 37, 2935. (b) Boden, C. D. J .; Pattenden, G.; Ye, T. Synlett 1995,
417. (c) Charette, A. B.; Chua, P. J . Org. Chem. 1998, 63, 908. (d)
Nishio, T. Tetrahedron Lett. 1995, 36, 6113. (e) Wipf, P.; Fritch, P. C.
Tetrahedron Lett. 1994, 35, 5397. (f) Lafargue, P.; Guenot, P.; Lel-
louche, J .-P. Synlett 1995, 171. (g) Mahler, S. G.; Serra, G. L.; Antonow,
D.; Manta, E. Tetrahedron Lett. 2001, 42, 8143. (h) Wipf, P.; Miller,
C. P.; Venkatraman, S.; Fritch, P. C. Tetrahedron Lett. 1995, 36, 6395.
(8) Lion, C.; Dubois, J . E. Tetrahedron 1973, 29, 3417.
10.1021/jo0355092 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/09/2004
J . Org. Chem. 2004, 69, 811-814
811