ORGANIC
LETTERS
2001
Vol. 3, No. 10
1519-1521
A Simple Preparation of Ketones.
N-Protected r-Amino Ketones from
r-Amino Acids
Lidia De Luca, Giampaolo Giacomelli,* and Andrea Porcheddu
Dipartimento di Chimica, UniVersita` degli Studi di Sassari, Via Vienna 2,
I-07100 Sassari, Italy
Received March 14, 2001
ABSTRACT
Carboxylic acids and amino acids are readily converted, under mild conditions, into the corresponding activated esters, which are reacted
with Grignard/CuI reagent to give the corresponding ketones in nearly quantitative yields. The compounds were recovered substantially pure
from the reaction mixtures.
N-Protected R-amino ketones are very important compounds
in synthetic organic chemistry. In fact, they are interesting
as intermediates in natural product synthesis1 and as starting
materials for nitrogen-containing heterocycles.2
amides.5 At present, this route might not suffer any more
from drawbacks since we have very recently reported an easy
one-flask procedure that allows one to obtain quantitatively
the amide without any purification.6 However, it requires a
large excess of the organometallic reagent.2,4
Several methods for the synthesis of R-amino ketones have
been reported starting from R-amino acids.3 Recently, a
conversion of R-amino acids into NH-Boc3d and NH-Cbz3e
protected R-amino ketones via imidazolides with Grignard
reagents under Cu(I) catalysis or by palladium-catalyzed
reaction of thiol esters with organozinc reagents, respectively,
were reported. The yields were in general satisfactory, but
the final product had to be purified on silica gel. A valuable
method to obtain ketones and in particular N-protected
R-amino ketones2,4 is based on the reaction between Grignard
or organolithium reagents and N-protected R-amino Weinreb
On this basis of and following our interest in the use of
[1,3,5]triazine derivatives in organic synthesis,7 we describe
herein an alternative approach that avoids the formation of
the Weinreb amide and provides an efficient and cheap
conversion of acids and in particular of R-amino acids into
the corresponding ketones via direct reaction with Grignard/
CuI reagents.
The procedure is based on the treatment of the carboxylic
acid with 2-chloro-4,6-dimethoxy[1,3,5]triazine (CDMT) and
N-methylmorpholine (NMM) in THF, which gives the
corresponding activated ester quantitatively in ca. 1 h
(monitored by TLC) at room temperature.6 After filtering
the white precipitate, 1 equiv of anhydrous CuI is added to
the solution, containing the activated ester, followed by 1
equiv of freshly prepared Grignard reagent, slowly and at 0
°C (Scheme 1).
(1) Overhand, M.; Hecht, S. M. J. Org. Chem. 1994, 59, 4721. Angle,
S. R.; Boyle, J. P. Tetrahedron Lett. 1995, 36, 6185.
(2) (a) Falorni, M.; Giacomelli, G.; Spanedda, A. M. Tetrahedron:
Asymmetry 1998, 9, 3039. (b) De Luca, L.; Falorni, M.; Giacomelli, G.;
Porcheddu, A. Tetrahedron 1999, 40, 8701.
(3) (a) Mayer, D. In Houben-Weyl, Methoden der Organischen Chemie,
4th ed.; Mu¨ller, E., Ed.; Thieme Verlag: Stuttgart, 1977; Vol. 7, 2c, p 2253.
(b) Fischer, L. E.; Muchowski, J. M. Org. Prep. Proced. Int. 1990, 22,
399. (c) Pace, R. D.; Kabalka, G. W. J. Org. Chem. 1995, 60, 4838. (d)
Bonini, B. F.; Comes-Franchini, M.; Fochi, M.; Mazzanti, G.; Ricci, A.,
Varchi, G. Synlett 1998, 1013. (e) Tokuyama, H.; Yokoshima, S.; Yamashita,
T.; Fukuyama, T. Tetrahedron Lett. 1998, 39, 3189.
(5) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(6) De Luca, L.; Giacomelli, G.; Taddei, M. J. Org. Chem. 2001, 66,
2534.
(7) Falorni, M.; Porcheddu, A.; Taddei, M. Tetrahedron Lett. 1999, 40,
4395. Falorni, M.; Giacomelli, G.; Porcheddu, A.; Taddei, M. J. Org. Chem.
1999, 64, 8962. Falchi, A.; Giacomelli, G.; Porcheddu, A.; Taddei, M.
Synlett 2000, 275.
(4) Sawamura, M.; Nakayama, Y.; Kato, T.; Ito, Y. J. Org. Chem. 1995,
60, 1727.
10.1021/ol015840c CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/17/2001