Simple one-flask method for the preparation of hydroxamic acids

Article abstract of DOI:10.1021/ol034903j

(Matrix presented) A one-step conversion of carboxylic acids to hydroxamic acids under very mild conditions is described. This simple and efficient method has been applied for the synthesis of enantiopure hydroxamate of α-amino acids and peptides.

Full text of DOI:10.1021/ol034903j

ORGANIC
LETTERS
2
003
Vol. 5, No. 15
715-2717
Simple One-Flask Method for the
Preparation of Hydroxamic Acids
2
Giampaolo Giacomelli,* Andrea Porcheddu, and Margherita Salaris
Dipartimento di Chimica, UniVersit a` degli Studi di Sassari, Via Vienna 2,
I-07100 Sassari, Italy
ggp@uniss.it
Received May 22, 2003
ABSTRACT
A one-step conversion of carboxylic acids to hydroxamic acids under very mild conditions is described. This simple and efficient method has
been applied for the synthesis of enantiopure hydroxamate of r-amino acids and peptides.
1
Hydroxamic acids are strong metal ion chelators and possess
a wide spectrum of biological activities with antibacterial,
antifungal, antiinflammatory, and anti-asthmatic properties,
tool, and there have been several reports describing syntheses
of hydroxamic acid derivatives. However, these methods
utilize highly expensive hydroxylamine reagents and some
of them are not commercially available.
7
2
etc. They also have been identified as potent inhibitors of
matrix metalloproteinases. O-Silylated hydroxamic acids
have been used for generating nitrile oxides under mild
conditions. Therefore, several methods have been developed
3
Thus, the economical way to obtain hydroxamic acid
8
derivatives remains the reaction of hydroxylamine with
4
9
esters or acid chlorides even if this last method cannot be
for the preparation of hydroxamic acids and have been well
documented in the literature. Hydroxamic acids have gener-
ally been synthesized in solution from nitro compounds or
through reaction of O/N-protected hydroxylamines such as
applied to amino acids. In this context, a one-step approach
was reported to use ethyl chloroformate as a carboxylic acid
activator. However, ethyl chloroformate is moisture sensi-
10
NH
2
-O-Bn, N-t-BOC-O-THP, N-t-BOC-O-TBDMS, N,O-bis-
(5) (a) Tamaki, K.; Ogita, T.; Tanzawa, K.; Sugimura, Y. Tetrahedron
Lett. 1993, 34, 683. (b) Altenburger, J. M.; Mioskowski, C.; d’Orchymont,
H.; Schirlin D.; Schalk, C.; Tarnus, C. Tetrahedron Lett. 1992, 33, 5055.
(phenoxycarbonyl)hydroxylamine, N,O-bis(tert-butoxycar-
bonyl)hydroxylamine and N,N,O-tris(trimethylsilyl)hydrox-
ylamine with activated carboxylic acids. Recently, hydroxamic
acids were obtained by treatment of N-acyloxazolidinones
with hydroxylamines using samarium triflate as a Lewis
(
c) Staszak, M. A.; Doecke, C. W. Tetrahedron Lett. 1994, 33, 6021. (d)
Ando, W.; Tsumaki, H. Synth. Commun. 1983, 13, 1053.
6) Sibi, M. P.; Hasegawa, H.; Ghorpade, S. R. Org. Lett. 2002, 4,
343.
(7) (a) Floyd, C. D.; Lewis, C. N.; Patel, S. R.; Whittaker, M. Tetrahedron
Lett. 1996, 37, 8045. (b) Richter, L. S.; Desai, M. C. Tetrahedron Lett.
5
(
3
6
acid. Solid-phase synthesis also has become an important
1997, 38, 321. (c) Chen, J. J.; Spatola, A. F. Tetrahedron Lett. 1997, 38,
1
551. (d) Mellor, S. L.; McGuire, C.; Chan, W. C. Tetrahedron Lett. 1997,
(
1) (a) Kurzak, B.; Kozlowski, H.; Farkas, E. Coord. Chem. ReV. 1992,
38, 3311. (e) Bauer, U.; Ho, W.; Koskinen, A. M. P. Tetrahedron Lett.
1997, 38, 7233. (f) Ngu, K.; Patel, D. V. J. Org. Chem. 1997, 62, 7088. (g)
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W.; Zhang, L.; Li, X.; Weigel, J. A.; Hall, S. E.; Mayer, J. P. J. Comb.
Chem. 2001, 3, 151.
(8) For a recent report on the synthesis of hydroxamic acids from
carboxylic acids, see: Bail e´ n, M. A.; Chinchilla, R.; Dodsworth, D. J.;
N a` jera, C. Tetrahedron Lett. 2001, 42, 5013.
(9) Pirrung, M. C.; Chau, J. H. L. J. Org. Chem. 1995, 60, 8084. (b)
Thouin, E.; Lubell, W. D. Tetrahedron Lett. 2000, 41, 457.
(10) Reddy, A. S.; Kumar, M. S.; Reddy, G. R. Tetrahedron Lett. 2000,
41, 6285.
1
3
14, 169. (b) Boukhris, S.; Souizi, A.; Robert, A. Tetrahedron Lett. 1996,
7, 179.
(
2) (a) Weber, G. Cancer Res. 1983, 43, 3466. (b) Miller, M. J. Acc.
Chem. Res. 1986, 19, 49. (c) Miller, M. J. Chem. ReV. 1989, 89, 1563.
3) (a) Whittaker, M.; Floyd, C. D.; Brown, P.; Gearing, A. J. H. Chem.
(
ReV. 1999, 99, 2735. (b) Cheng, M.; De, B.; Pikul, S.; Almstead, N. G.;
Natchus, M. G.; Anastasio, M. V.; McPhail, S. J.; Snider, C. E.; Taiwo, Y.
O.; Chen, L.; Dunaway, C. M.; Gu, F.; Dowty, M. E.; Mieling, G. E.; Janusz,
M. J.; Wang-Weigand, S. J. Med. Chem. 2000, 43, 369 and references
therein.
(4) Muri, D.; Bode, J. W.; Carreira, E. M. Org. Lett. 2000, 2, 539.
1
0.1021/ol034903j CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/02/2003

tive and its vapor is a powerful irritant, particularly to the
respiratory system and to the eyes.
Table 1. Conversion of Carboxylic Acids into the
Following our interest in the use of [1,3,5]triazine deriva-
tives in organic synthesis,11 we wish to report here a new
simple, mild, and high-yielding one-flask synthesis of
hydroxamic acids from carboxylic acids and N-protected
amino acids that uses the very cheap 2,4,6-trichloro[1,3,5]-
triazine (cyanuric chloride, TCT) as a coupling agent
Corresponding Hydroxamic Acids
12
(Scheme 1).
Scheme 1
The method allows the preparation of hydroxamic acids
in a single-step reaction. Thus, a carboxylic acid is treated
with TCT (0.3 equiv), N-methylmorpholine (NMM) (1 equiv)
2 2
in CH Cl , and dimethylamino pyridine (DMAP) as a catalyst
(0.1 equiv), followed by hydroxylamine hydrochloride (1.1
equiv) in dichloromethane. Stirring is continued at room
temperature until complete conversion of the carboxylic acid
(monitored by TLC). The reaction mixture is filtered on
Celite and washed with diluted HCl and brine.
The desired product is recovered in pure form and in high
yields simply by concentration of the CH Cl extracts at
2 2
reduced pressure (Table 1). The triazine byproducts are easily
removed by this simple aqueous workup. The reaction is not
fast and requires from 6 to 12 h for completion in most cases.
However, this method can be also successfully applied on a
large scale.
The yields are high in all cases examined, and no
O-acylated or di- and triacylated products were found in the
reaction mixture. As shown from the results reported in Table
1, the method is compatible with the common N-protecting
groups and no deprotection was noted even with the less
stable Boc-N-protected amino acids. The reaction can be
carried out in DMF as a solvent with the same results and
comparable yields.
The data collected show that no significant racemization
of the chiral center on the R-carbon atom occurred during
the synthesis. In fact, a sample of (S)-N-Boc-phenylglycine,
2
5
[R]
D
+145 (c 1, ethanol) gave (S)-N-Boc-phenylglycine
(
11) (a) Falorni, M.; Porcheddu, A.; Taddei, M. Tetrahedron Lett. 1999,
4
0, 4395. (b) Falorni, M.; Giacomelli, G.; Porcheddu, A.; Taddei, M. J.
hydroxamate, 17, [R]25
Analogously, (S)-N-Boc-proline, [R]
gave (S)-N-Boc-proline hydroxamate, 9, [R]
methanol), according to literature data.
13
D
+46.1 (c 0.2, methanol), ee >99%.
Org. Chem. 1999, 64, 8962. (c) Falchi, A.; Giacomelli, G.; Porcheddu, A.;
Taddei, M. Synlett 2000, 275. (d) De Luca, L.; Giacomelli, G.; Taddei, M.
J. Org. Chem. 2001, 66, 2534. (e) De Luca, L.; Giacomelli, G.; Porcheddu,
A. Org. Lett. 2001, 3, 1519. (f) De Luca, L.; Giacomelli, G.; Porcheddu,
A. Org. Lett. 2001, 3, 3041. (g) De Luca, L.; Giacomelli, G.; Porcheddu,
A. Org. Lett. 2002, 4, 553. (h) De Luca, L.; Giacomelli, G.; Porcheddu, A.
J. Org. Chem. 2002, 67, 5152. (i) De Luca, L.; Giacomelli, G.; Porcheddu,
A. J. Org. Chem. 2002, 67, 6272. (j) De Luca, L.; Giacomelli, G.; Masala,
S.; Porcheddu, A. J. Org. Chem. 2003, 68, 4999-5001.
2
0
D
-61.1 (c 1, AcOH)
2
5
D
-57.1 (c 1,
14
(13) Determined by analysis of the 19F NMR spectra of the corresponding
MPTA derivatives [Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem.
1969, 34, 2543] of both racemic and optically active Boc-phenylglycine
1
(12) Reaction conducted on free amino acids produces the corresponding
hydroxamates. H NMR analysis on the hydroxamates carried out in the
hydroxamate in very low yields (<10%), and the final products are not
easily recovered from the reaction mixture.
presence of Eufod3 gave analogous results.
(14) Thouin, E.; Lubell, W. D. Tetrahedron Lett. 2000, 41, 457.
2716
Org. Lett., Vol. 5, No. 15, 2003

Moreover, the method seems to be directly applicable to
the synthesis of peptide hydroxamic acids, as demonstrated
by the preparation of the model dipeptide hydroxamic acids
of Figure 1.
2 2
(0.01 g, 0.1 mmol) in CH Cl (20 mL), containing hydroxy-
lamine hydrochloride (0.68 g, 9.8 mmol), stirred, and
maintained at 0 °C. After the addition, the mixture was
warmed to room temperature, stirred for 12 h, and then
filtered on Celite, and the organic phase was washed three
times with 15 mL of 1 N HCl and then brine. The organic
layers were dried (Na
2 4
SO ) and the solvent evaporated to
yield compound 3 that was isolated without other purifica-
25
14 1
tions (2.3 g, 96%), [R]
D
-46.1 (c 0.5, methanol): HNMR
δ 8.06 (s, 1H), 7.26-7.36 (m, 5H), 5.34 (s, 2H), 4.29 (t,
13
1
H), 3.35 (t, 2H), 2.17 (s, 1H), 1.60-1.83 (m, 4H); CNMR
δ 170.0, 155.8, 137.0, 128.4, 127.8, 127.5, 67.0, 60.2, 40.9,
2
3.7, 20.1.
In conclusion, we think that the one-flask method de-
scribed here is one of the most simple and convenient for
the preparation of hydroxamic acids, even in large scale, as
it uses friendly reaction conditions and inexpensive reagents.
The method can be used as a valid alternative to other ones,
Figure 1.
15
5
Thus, compounds 18 and 19 were prepared with 73 and
thereby avoiding the use of N-protected hydroxylamine and
8
2% overall yields, respectively, and recovered without any
consequently any tedious subsequent deprotection reaction
or purification.
further purification.
The procedure for the preparation of (S)-(N-benzyloxy-
carbonyl)proline hydroxamate, 3, is representative for all
cases. Cyanuric chloride (TCT, 0.5 g, 3.0 mmol) was added
to a solution of (S)-(N-benzyloxycarbonyl)proline (2.24 g,
Acknowledgment. The work was financially supported
by the University of Sassari (Fondi MIUR ex 40% 2001).
Supporting Information Available: Physical and spec-
troscopic data for all unknown compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
9.0 mmol), NMM (1.0 g, 1.1 mL, 9.9 mmol), and DMAP
(15) Odake, S.; Nakahashi, K.; Morikawa, T.; Takebe, S.; Kobashi, K.
Chem. Pharm. Bull. 1992, 40, 2764.
OL034903J
Org. Lett., Vol. 5, No. 15, 2003
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