2534
J . Org. Chem. 2001, 66, 2534-2537
and O-benzyl- or tert-butyldiphenylsilyl hydroxylamine11
An Ea sy a n d Con ven ien t Syn th esis of
for hydroxamates). Stirring is continued for 8 h at room
temperature. The reaction mixture is diluted with ether
and then washed with water, aqueous Na2CO3, diluted
HCl, and brine. The desired product is recovered in pure
form, simply by concentration of the ether extracts at
reduced pressure.
Wein r eb Am id es a n d Hyd r oxa m a tes
Lidia De Luca, Giampaolo Giacomelli,* and
Maurizio Taddei
Dipartimento di Chimica, Universita` degli Studi di Sassari,
Via Vienna 2, I-07100 Sassari, Italy
As shown in Table 1, a variety of N-methoxy-N-methyl
amides were prepared from commercially available car-
boxylic acids and amino acids (method A). In all cases,
the yields were quantitative and the conversion very
high: the product can be recovered pure without any
supplementary purification, as the unreacted acid was
separated during the workup of the reaction mixture.
This methodology is applicable to the synthesis of other
O-alkylhydroxamates (6 and 10, entries 10 and 16) and
to the preparation of O-silyl hydroxamates too. In this
last case it is noteworthy that the method allows an easy
preparation of O-silyl hydroxamates derived from R-ami-
no acids.12 The previous syntheses of O-silyl hydrox-
amates started, in fact, from the corresponding acyl
chlorides, preventing the preparation of compounds as 9
(Table 1).
Taking into account that CDMT may be an irritating
agent for eyes and nose, we checked the possibility of
using 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmor-
pholinium chloride (DMTMM)13 (Table 1, method B).
Even with this reagent the final products were exclu-
sively the desired Weinreb amides, which can be recov-
ered pure after the simple aqueous workup of the
mixture. However, the condensation of the acids with
DMTMM requires longer times due to the formation of
the activated ester (1.5 h). Moreover, the reactions carried
out in the presence of DMTMM proceeded, under the
conditions employed (8 h of stirring at room tempera-
ture), with conversions lower than those performed with
CDMT, with the exception of the reaction with 2-ni-
trobenzoic acid. In any case, the reactions can be forced
to the completion by prolonging the reaction time.
The synthesis of Weinreb amides can be achieved even
with the very cheap cyanuric chloride as condensating
agent, but the reaction occurs very slowly if conducted
following the one-flask procedure, probably owing to the
various salts present in the mixture. The reaction can
be accelerated by filtering off the precipitate formed on
Celite and transferring the THF solution, containing the
activated ester, into a flask containing the N,O-dimeth-
ylhydroxylamine hydrochloride THF suspension (Table
1, entry 3).
ggp@ssmain.uniss.it
Received J anuary 15, 2001
The so-called Weinreb amides1 (or N-methoxy-N-meth-
yl amides) are versatile building blocks in organic
synthesis.2 Their preparation can be accomplished by
coupling carboxylic acids and N,O-dimethylhydroxyl-
amine. The majority of the methods reported uses peptide
coupling reagents such as chloroformates,3 BOP,4 DCC,5
and others6 or phosphonic derivatives.7 These reactives
are expensive in some cases, and the removal of their
excess (and/or the removal of byproducts) from the
reaction mixtures may be difficult. Additional purification
of the reaction product is often required. The importance
of Weinreb amides is attested by a recent communication
describing a one-flask synthesis of Weinreb amides of
carboxylic and amino acids using a Deoxo-Fluor fluori-
nating reagent.8 Although simple, this method requires
the use of an expensive reagent. Moreover, the crude
products must be separated by column chromatography.
Following our interest in the use of [1,3,5]triazine
derivatives in organic synthesis,9 we report here a new
simple and high-yielding one-flask synthesis of Weinreb
amides from carboxylic acids and N-protected amino
acids that uses different [1,3,5]triazine derivatives as the
coupling agents. The method allows the preparation of
Weinreb amides and hydroxamates as O-benzyl and
O-silyl hydroxamates10 that can be easily transformed
into hydroxamic acids.
Treating a carboxylic acid with 2-chloro-4,6-dimethoxy-
[1,3,5]triazine (CDMT) and N-methylmorpholine (NMM)
in THF, the corresponding activated ester is quantita-
tively formed in 1 h (monitored by TLC). This white
suspension, containing the activated ester, is subse-
quently treated with the required hydroxylamine deriva-
tive (N,O-dimethylhydroxylamine for the Weinreb amide
(1) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(2) Lucet, D.; Le Gall, T.; Moskowski, C.; Ploux, O.; Marquet, A.
Tetrahedron: Asymmetry 1996, 7, 985.
Significant racemization of the chiral center of the
R-amino acids did not occur under the conditions em-
ployed, as revealed by the optical rotation values of the
products 10 and 12 if compared with those reported in
the literature14,15 (entries 15 and 17).
(3) Falorni, M.; Giacomelli, G.; Spanedda, A. M. Tetrahedron:
Asymmetry 1998, 9, 3039.
(4) Maugras, I.; Poncet, J .; J ouin, P. Tetrahedron 1990, 46, 2807.
Shreder, K.; Zhang, L.; Goodman, M. Tetrahedron Lett. 1998, 39, 221.
(5) Braun, M.; Waldmu¨ller, D. Synthesis 1989, 856.
(6) Sibi, M. P.; Stessman, C. C.; Schultz, J . A.; Christensen, J . W.;
Lu, J .; Marvin, M. Synth. Commun. 1995, 25, 1255.
(7) Oppolzer, W.; Cunningham, A. F. Tetrahedron Lett. 1986, 27,
5467; Dechantsreiter, M. A.; Burkhart, F.; Kessler, H. Tetrahedron Lett.
1998, 39, 253; Einhorn, J .; Einhorn, C.; Luche, J . L. Synth. Commun.
1990, 20, 1105.
(8) Tunoori, A. R.; White, J . M.; Georg, G. I. Org. Lett. 2000, 2, 4091.
(9) 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.
(11) Denmark, S. E.; Dappen, M. S.; Sear, N. L.; J acobs, R. T. J .
Am. Chem. Soc. 1990, 112, 3466.
(12) O-Silyl hydroxamates are valuable intermediates for the ge-
naration of nitrile oxides in solution. See: Muri, D.; Bode, J . W.;
Carreira, E. M. Org. Lett. 2000, 2, 539.
(13) Kunishima, M.; Kawachi, C.; Morita, J .; Terao, K.; Iwasaki, F.;
Tani, S. Tetrahedron 1999, 55, 13159.
(14) Saari, W. S.; Fisher, T. E. Synthesis 1990, 453.
(15) Sibi, M. P.; Stessman, C. C.; Schultz, J . A. Synth. Commun.
1995, 25, 1255.
(10) Papaioannou, D.; Barlos, K.; Francis, G. W.; Brekke, T.; Aksnes,
D. W.; Maartmann-Moe, K. Acta Chem. Scand. 1990, 44, 189.
10.1021/jo015524b CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/10/2001