A convenient method for the preparation of hydroxamic acids

Article abstract of DOI:10.1016/S0040-4039(00)01058-3

A one-step conversion of carboxylic acid to hydroxamic acid, under neutral pH conditions is described. This simple, selective and efficient method was applied to a wide range of aliphatic/aromatic carboxylic acid derivatives that contain hydroxyl, halo, ester and other base sensitive groups as substituents. The method utilizes cheaply available reagents and hence it is a practical and cost effective strategy, compared to the other methods available in the literature. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01058-3

Tetrahedron Letters 41 (2000) 6285±6288
A convenient method for the preparation of
hydroxamic acids
A. Sekar Reddy, M. Suresh Kumar and G. Ravindra Reddy*
Medicinal Chemistry & Drug Discovery Group, Penn Bio-Organics, Inc., 1981 Pine Hall Drive, State College,
PA 16801, USA
Received 11 April 2000; revised 12 June 2000; accepted 13 June 2000
Abstract
A one-step conversion of carboxylic acid to hydroxamic acid, under neutral pH conditions is described.
This simple, selective and ecient method was applied to a wide range of aliphatic/aromatic carboxylic
acid derivatives that contain hydroxyl, halo, ester and other base sensitive groups as substituents. The
method utilizes cheaply available reagents and hence it is a practical and cost e€ective strategy, compared
to the other methods available in the literature. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: hydroxamic acid; metalloenzymes; carboxylic acid and antibiotics.
Hydroxamic acid derivatives possess a wide spectrum of biological activities such as anti-
in¯ammatory, antiasthmatic, antimetastatic, antibiotic, psychotropic, insecticidal, acaricidal and
nematocidal activity.1a e They also inhibit various other enzymes such as metalloenzymes.2
Several methods are available for the preparation of hydroxamic acids and have been well-
documented in the literature.3a j The common method for the preparation of these compounds is via
the reaction of O/N-protected hydroxylamine such as NH2-O-Bn, N-t-BOC-O-THP, N-t-BOC-O-
TBDMS, N,O-bis(phenoxycarbonyl)hydroxylamine, N,O-bis(tert-butoxycarbonyl)hydroxylamine
and N,N,O-tris(trimethylsilyl)hydroxylamine with activated carboxylic acids.4a d However, these
methods utilize highly expensive hydroxylamine reagents and some of them are not commercially
available. The economical way of making hydroxamic acid derivative is the reaction of
hydroxylamine with acid chlorides or esters.5
Preparation of acid chlorides is often tedious when other acid labile functional groups present
in the substrate. Also, it will be very dicult to prevent further acylation during the reaction with
hydroxylamine. In our experience, reaction of hydroxylamine with esters does not proceed under
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01058-3

6286
neutral conditions (Scheme 1); it always needs an alkaline condition (pH>10). Hence, this
method is not suitable if one needs to perform this reaction on ester derivatives that contain
halides, esters and other base-sensitive groups.
Scheme 1.
As a part of our drug discovery program we needed to make the hydroxamic acid derivatives
from the corresponding carboxylic acid derivatives. None of the literature methods mentioned
above gave the required product in good yield when using hydroxylamine. Therefore, we have
developed a mild and simple one-step approach for the preparation of hydroxamic acids from
carboxylic acid derivatives as shown in Scheme 2.
Scheme 2.
A typical experimental procedure is as follows: To a solution of the isobutyric acid (0.88 g, 10
mmol) in diethylether (30 mL) at 0ꢀC ethylchloroformate (1.3 g, 12 mmol) and N-methylmorpholine
(1.3 g, 13 mmol) were added and the mixture was stirred for 10 min. The solid was ®ltered o€ and
the ®ltrate was added to freshly prepared hydroxylamine (0.5 g, 15 mmol) in methanol.6 The
reaction mixture was stirred at room temperature for 15 min. The solvent was evaporated and the
residue was puri®ed by silica gel column chromatography to obtain the isobutyrohydroxamic
acid (0.83 g, 81%).
Further, the method was successfully extended to the synthesis of a variety of hydroxamic acid
derivatives from the carboxylic acids under neutral conditions. In all cases, the yields were higher
than 80% (Table 1). In addition, by-products such as N, O and triacylated derivatives that are
usually formed in the reaction of acid chlorides with hydroxylamine were not observed in this case.
Hence, this method is simple, selective and works equally well with aliphatic/aromatic carboxylic
acid derivatives that contain hydroxyl, halo and ester groups as additional substituents.
In order to establish the reaction pathway, the reaction of methylhexanoate with
hydroxylamine in methanol (pH=7) was performed at room temperature for 24 h. Surprisingly,
no trace of the corresponding hydroxamic acid was found and the whole starting material was
recovered. Based on the above result the formation of methylester intermediate was ruled out and
the formation of the hydroxamic acid derivative could proceed via anhydride 2 (Scheme 2).
This method is simple and convenient as it does not require any crucial work-up of the reaction
that involves acidi®cation with resins5 or making a copper complex and liberation with H2S.7 We also
found that this method works equally well with triethylamine in the place of N-methylmorpholine.
In conclusion, we report a mild and ecient method for the preparation of hydroxamic acid
derivatives under neutral pH conditions, that is suitable for a variety of substituted carboxylic

6287
Table 1
Preparation of hydroxamic acids from hydroxylamine and carboxylic acids
acids. Application of this methodology to the chiral carboxylic acids and synthesis of natural
product is in progress.
Acknowledgements
The authors wish to thank Penn Bio-Organics, Inc. for ®nancial support and encouragement.
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