An expeditious hydroxyamidation of carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2005.05.131

Capitalizing on in situ activation with the cyclic phosphonic anhydride PPAA (1), the conversion of carboxylic acids into hydroxamic acids has been reduced to an experimentally simple one-pot operation that addresses the issue of polyacylation without resorting to a large excess of hydroxylamine or to protection. Scope and selectivity were satisfactory with a wide range of substrates, including α,β-unsaturated acids and hydroxyacids.

Full text of DOI:10.1016/j.tetlet.2005.05.131

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5113–5115
An expeditious hydroxyamidation of carboxylic acids
Abdellah Ech-Chahad, Alberto Minassi, Luca Berton and Giovanni Appendino*
`
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Universita del Piemonte Orientale,
Via Bovio 6, 28100 Novara, Italy
Received 11 May 2005; accepted 31 May 2005
Available online 17 June 2005
Abstract—Capitalizing on in situ activation with the cyclic phosphonic anhydride PPAA (1), the conversion of carboxylic acids into
hydroxamic acids has been reduced to an experimentally simple one-pot operation that addresses the issue of polyacylation without
resorting to a large excess of hydroxylamine or to protection. Scope and selectivity were satisfactory with a wide range of substrates,
including a,b-unsaturated acids and hydroxyacids.
Ó 2005 Elsevier Ltd. All rights reserved.
The past decade has seen the resurrection of interest for
hydroxamic acids, spurred by the occurrence of a key N-
hydroxyamide motif in an array of bioactive compounds
that includes zinc-protease inhibitors of oncological and
anti-inflammatory relevance,1 microbial siderophores,2
and the antibiotic phosphidomycin, a powerful antima-
larial agent that inhibits the non-mevalonate biosynthe-
sis of isoprenoids.3
dle for their lability (arachidonic, ximeninic, retinoic),
and, by avoiding an excess hydroxylamine, turned out
to be of general applicability also to polyfunctionalized
and a,b-unsaturated substrates.
We reasoned that the chemoselectivity issue in the acyl-
ation of hydroxylamine is somewhat similar to that
plaguing the acylation of phenolic amines, the underly-
ing common problem being the presence of an acidic
oxygen function that can be activated in terms of nucleo-
philicity by deprotonation. In a previous study, we dis-
covered that mixed phosphoric anhydrides show very
low reactivity toward oxygen functions, and identified
the cheap cyclic anhydride PPAA (=T3P, 1)11 as a supe-
rior, traceless, and environmentally benign promoter for
the N-acylation of phenolic amines.12 Given the similar
chemoselectivity problem, we wondered if this acylation
protocol could be extended also to hydroxylamine.
Despite continuous progress in amide bond formation,
the synthesis of hydroxamic acid and their derivatives
has not significantly advanced over the past years, and
still relies on protocols that offer potential for improve-
ment, especially when applied to the parent compounds.
Acylation of hydroxylamine under carbodiimide promo-
tion is plagued by N,O-diacylation even with sub-stoi-
chiometric amounts of acids.4 To overcome this
problem, ex situ activation of carboxylic acids (chlo-
rides,5 mixed anhydrides,6 esters,7 oxazolidinones8), O-
protection of hydroxylamine9, and a large excess of it
have been employed alone, or more often, in combina-
tion. Faced with the problem of preparing a library of
fatty acid hydroxamates to assay against various pro-
teins of the endocannabinoid system,10 we have devel-
The reaction was investigated with oleic acid, whose
hydroxamate can inhibit the degradation of the endo-
genous sleep factor oleamide.13 The reported synthetic
protocol13 involves ex situ activation to oleyl chloride
and ex situ deprotonation of an excess hydroxylamine
hydrochloride, and its overall yield (45%) served as a
yardstick for our investigations.
oped a practical solution to the problem. Our
hydroyxyamidation protocol provided an expeditious
entry into the N-hydroxyamides of acids difficult to han-
Attempts to translate the original conditions for the
acylation of phenolic amines to hydroxylamine
(1.2 equiv PPAA, stoichiometric acid-to-amine ratio,
in situ de-salification of the amine hydrochloride with
triethylamine (TEA), and dichloromethane as the
solvent)12 gave excellent results in terms of chemoselec-
tivity, but only a modest yield (25%), essentially due to a
Keywords: Hydroxamic acids; Hydroxyamidation; Fatty acids, PPAA;
Oleic acid.
*
Corresponding author. Tel.: +39 0321 375744; fax: +39 0321
375621; e-mail: giovanni.appendino@pharm.unipmn.it
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.131

5114
A. Ech-Chahad et al. / Tetrahedron Letters 46 (2005) 5113–5115
Table 1. Hydroxyamidation of oleic acid under various conditions
O
P
O
P
O
P
O
O
O
H
N
1
OH
5
OH
5
5
5
NH2OH.HCl
O
O
Entry
NH2OHÆHCl (equiv)
Solvent
Yield (%)a
1
2
3
4
5
1
2
2
1
2
CH2Cl2
CH2Cl2
EtOAc
35
41
53
76
85
CH3CN
CH3CN
a All reaction were carried out at room temperature with 1.2 mol equiv PPAA, and were quenched after stirring overnight. Yields were calculated
after gravity column chromatography purification of the reaction mixture. Differences in yield essentially reflect differences in conversion, the
remaining mass balance being starting oleic acid.
Table 2. Hydroxyamidation of various carboxylic acids
low conversion. A first upgrade to 35% yield was
achieved by delaying (ca. 30 min) the addition of
hydroxylamine hydrochloride to the acid–PPAA–TEA
mixture, thus avoiding partial quenching of PPAA by
hydroxylamine (Table 1),14 while a 1:2 acid to hydroxyl-
amine ratio accelerated the reaction, with, however, only
a modest effect in yield. The insolubility of hydroxyl-
amine hydrochloride in dichloromethane was a further
point of improvement, since a change to acetonitrile
eventually provided a homogeneous reaction mixture
and a beneficial effect in yield. After dilution of the reac-
tion mixture with ethyl acetate, washing with brine, and
evaporation, the reaction mixture, still containing unre-
Entry
Hydroxamate product
Yield (%)a
H
N
(
)
6
(
)
OH
1
2
85
77
5
O
H
N
(
)
13
OH
OH
O
O
H
N
3
4
5
(
)
85
70
72
6
H
N
(
(
)
3
)
OH
4
OH
O
1
H
N
acted acid (ca. 6% by H NMR analysis), was crystal-
lized from hexane, affording N-hydroxyoleamide in
72% yield.
)
(
(
)
OH
6
9
O
O
OH
N
H
6
7
52
68
Alternatively, unreacted oleic acid could be removed by
chromatography on silica gel, affording N-hydroxyole-
amide in 85% yield. Attempts to drive the reaction to
completion failed even with a large excess (10 mol equiv)
of hydroxylamine, suggesting that minor amounts of
oleyl anhydride might be formed in the activation step.
Subsequent anhydride aminolysis would then waste
one equivalent of acylating agent as a carboxylate leav-
ing group. The 30-min delay between the addition of
hydroxylamine to the PPAA–carboxylic acid mixture
seems therefore an optimal time compromise to mini-
mize carboxylic anhydride formation and prevent the
partial quench of unreacted PPAA by hydroxylamine.14
H
N
(
)
( )
OH
5
4
O
O
OH
O
8
9
57
72
N
H
O
OH
N
H
OH
10
11
45
52
N
H
O
To investigate the scope and selectivity of the reaction,
the optimized protocol15 was next applied to a variety
of carboxylic acids. The range of substrates successfully
hydroxyamidated includes (Table 2) polyunsaturated
acids, both skipped (arachidonic acid, entry 6) and con-
jugated (ximeninic acid, entry 7), a,b-unsaturated acids
(2-octinoic acid, sorbic acid, retinoic acid, methacrylic
acid, entries 8, 9, 10, 11, respectively), and unprotected
hydroxyacids (ricinoleic acid, entry 4 and the sterically
hindered triterpenoid glycyrrhetic acid, entry 12).16 Aro-
matic acids like benzoic acid (entry 13) gave only modest
yield, as already noticed with that of oxyamidation pro-
tocols (Table 2).8,17
OH
N
H
O
C
OH
N
H
H
O
12
13
64
56
H
HO
H
H
O
OH
N
H

A. Ech-Chahad et al. / Tetrahedron Letters 46 (2005) 5113–5115
5115
in dichloromethane gave the N,O-diacyl derivative as the
only reaction product, and even with a very large excess
(10-fold) of hydroxylamine hydrochloride, a ca. 3:1
mixture (1H NMR analysis) of mono- and diacyl deriv-
atives was obtained.
The mechanistic rationale for the reluctance of mixed
phosphonic anhydrides to react with oxygen nucleophiles
is unclear, but it does not seem unreasonable to assume
that the negative charge of the intermediate phosphonic
anhydride contributes to repel attack from negatively
charged oxygen functions, while seemingly having only
a minor effect on neutral nitrogen nucleophiles.
5. Devlin, J. P.; Ollis, W. D.; Thorpe, J. E. J. Chem. Soc.,
Perkin Trans. 1 1975, 846–848.
6. Reddy, A. S.; Kumar, M. S.; Reddy, G. R. Tetrahedron
Lett. 2000, 41, 6285–6288.
In conclusion, by combining the in situ activation of car-
boxylic acids to mixed phosphoric anhydrides and the
generation of hydroxylamine from its corresponding
and air stable hydrochloride, the conversion of carbox-
ylic acids to hydroxamic acids has been reduced to an
experimentally simple one-pot operation, that avoids
ex situ processes (derivatization of the acid, de-salifica-
tion of hydroxylamine), and addresses the issue of poly-
acylation without resorting to an excess hydroxylamine
or to its protection. The method is especially suitable
for labile substrates, whose activation via chloride is
not trivial, for a,b-unsaturated acids that do not tolerate
large excesses of hydroxylamine, and for hydroxyacids,
whose oxyamidation with other protocols would require
hydroxyl protection.
7. Fieser, L. F.; Feiser, M. In Reagents for Organic Synthesis;
J. Wiley and Sons: New York, 1967; Vol. 1, pp 478–479.
8. Sibi, M. P.; Hasegawa, H.; Ghorpade, S. R. Org. Lett.
2002, 4, 3343–3346.
9. Sandler, S. R.; Karo, W. In Organic Functional Group
Preparations; Academic Press: New York, 1983; Vol. 3, pp
482–522.
10. Di Marzo, V.; Bifulco, M.; De Petrocellis, L. Nature Rev.
Drug Discov. 2004, 3, 771–784.
11. Schwarz, M. Synlett 2000, 1369.
12. Appendino, G.; Minassi, A.; Schiano Morello, A.; De
Petrocellis, L.; Di Marzo, V. J. Med. Chem. 2002, 45,
3739–3745.
13. Patterson, J. E.; Ollmann, I. R.; Cravatt, B. F.; Boger, D.
L.; Wong, C.-H.; Lerner, R. A. J. Am. Chem. Soc. 1996,
118, 5938–5945.
14. Reverse addition of a carboxylic acid to a mixture of
PPAA, hydroxylamine, and TEA, gave a lower hydr-
oxamate yield (16% with oleic acid) compared to the
direct addition, suggesting a certain competition between
carboxylate and hydroxylamine for phosphonylation.
15. Typical experimental procedure: To a stirred solution of
PPAA (50% in EtOAc, 1.2 mol. equiv) in acetonitrile (ca.
5 mL/mMol of acid) triethylamine (4 mol equiv) and the
carboxylic acid were added. After stirring 30 min at room
temp., hydroxylamine hydrochloride (2 mol equiv) was
added, and stirring was continued overnight at room
temp. The reaction was then worked up by dilution with
EtOAc and washing with brine. The organic phase was
dried (Na2SO4) and evaporated, and the residue was either
crystallized from hexane or purified by gravity column
chromatography on silica gel. All compounds were
Acknowledgements
We thank MIUR (Fondi ex-40%, Project: Chemorecezi-
`
one Gustativa. Sintesi e Relazioni Attivita-Struttura di
Molecole Attive sul Sapore) for financial support.
References and notes
1. For recent reviews on hydroxamate inhibitors of prote-
ases, see: Whittaker, M.; Floyd, C. D.; Brown, P.;
Gearing, A. J. H. Chem. Rev. 1999, 99, 2735–2776;
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2000, 83, 1685–1692.
2. Roosemberg, J. M.; Miller, M. J. J. Org. Chem. 2000, 65,
4833–4838.
3. Wiesner, J.; Ortmann, R.; Jomaa, H.; Schlitzer, M. Angew.
Chem., Int. Ed. 2003, 42, 5274–5293.
1
characterized by H- and 13C NMR, IR and ESI-MS.
16. However, attempts to oxyamidate betulinic acid, an even
more encumbered triterpenoid substrate, failed.
17. Since p-methoxy- and p-nitrobenzoic acids gave yields
similar to that of benzoic acid, the origin of this effect is
unclear.
4. For instance, treatment of oleic acid with a twofold molar
excess of hydroxylamine hydrochloride and triethylamine