A. Volonterio, M. Zanda / Tetrahedron Letters 44 (2003) 8549–8551
8551
The structures of some of the hydantoin products, such
as 8k and 8l, were confirmed by correlation with the
compounds described in the literature.7
Soloshonok, V. A., Eds.; Wiley: Chichester, 1995; (b)
Sutherland, A.; Willis, C. L. Nat. Prod. Rep. 2000, 621–
631.
4. Sheehan, J. C.; Hess, G. P. J. Am. Chem. Soc. 1955, 77,
1067–1068.
5. For a review, see: Klausner, Y. S.; Bodansky, M. Synthe-
sis 1972, 1, 453–463.
6. See for example: (a) Kishikawa, K.; Yamamoto, M.;
Kohmoto, S.; Yamada, K. J. Org. Chem. 1989, 54,
2428–2432; (b) Kohmoto, S.; Miyaji, Y.; Tsuruoka, M.;
Kishikawa, K.; Yamamoto, M.; Yamada, K. J. Chem.
Soc., Perkin Trans. 1 2001, 2082–2088; (c) Anglada, J.
M.; Campos, T.; Campos, F.; Camps, F. M.; Moreto, J.
M.; Pages, L. J. Heterocycl. Chem. 1996, 33, 1259–1270;
(d) Hoskins, W. M.; Crout, D. H. G. J. Chem. Soc,.
In order to gain a deeper insight into the mechanism of
this domino process, the reaction between 1d and 5b
(see Table 1, entry 10) was performed in an NMR tube.
1
Unfortunately, neither H nor 13C NMR spectroscopy
allowed us to detect any putative intermediate such as 6
or 7 (Scheme 3), since the final hydantoin 8i formed
very rapidly.
In summary, we have described a new domino reaction
effectively producing aspartic-acid derived hydantoins 8
from carbodiimides 1 and activated a,b-unsaturated
acids 5. The process is operationally very simple, fast,
employs easily available reagents and can be used to
produce arrays of structurally diverse hydantoins,
including fluorinated ones. Extension of the reaction to
other activated a,b-unsaturated carboxylic acids, and a
stereoselective version of the process are currently being
investigated.
Perkin Trans.
1 1977, 538–544; (e) Bernasconi, S.;
Comini, A.; Corbella, A.; Gariboldi, P.; Sisti, M. Synthe-
sis 1980, 385–387; (f) Xi, Z.; Agback, P.; Sandstro¨m, A.;
Chattopadhyaya, J. Tetrahedron 1991, 47, 9675–9690.
7. A conceptually related process involving fumaric acid
monomethyl ester and several carbodiimides, in the pres-
ence of alcohols and amines, was reported to produce
rearranged urea products via the intermediates 6 and 7.
In that case, the corresponding hydantoins were occa-
sionally observed as minor byproducts. See: Kishikawa,
K.; Sankhavasi, W.; Yoshizaki, K.; Kohmoto, S.;
Yamamoto, M.; Yamada, K. J. Chem. Soc., Perkin
Trans. 1 1994, 1205–1209. No attempts to produce
hydantoins and no description of the reaction course in
the absence of alcohols or amines were described therein.
8. 2-Imino-oxazolidin-5-ones 7 have been described and iso-
lated: Brady, W. T.; Owens, R. A. J. Org. Chem. 1977,
42, 3220–3222.
Acknowledgements
We thank MIUR (Cofin 2002, Project ‘Peptidi Sintetici
Bioattivi’), Politecnico di Milano and C.N.R. for eco-
nomic support.
References
9. The use of a catalytic base (DMAP or sym-collidine) did
not improve the outcome of the reactions involving 5d.
10. A sample of diastereomerically pure Z-5a was obtained
by flash chromatography (n-Hex/EtOAc 8:2) of the mix-
ture.
1. See for example: Zhang, W.; Lu, Y. Org. Lett. 2003, 5,
2555–2558 and references cited therein.
2. Tietze, L. F. Chem. Rev. 1996, 96, 115–136.
3. For an overview of the field, see: (a) Fluorine-containing
Amino Acids: Synthesis and Properties; Kukhar, V. P.,