Simple syntheses of hydroxamic acids and their conversion into α- hydroxy and α-amino acids

Article abstract of DOI:10.1016/S0040-4039(00)00228-8

The nucleophilic ring opening of gem-dicyanoepoxides by LiBr or Li₂NiBr₄, in the presence of hydroxylamine derivatives leads to new α-halo hydroxamic acids. These compounds has been used in the synthesis of α- functionalized hydroxamic acids, α-hydroxy and α-amino acids in good yields.

Full text of DOI:10.1016/S0040-4039(00)00228-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2559–2562
Simple syntheses of hydroxamic acids and their conversion into
α-hydroxy and α-amino acids
Saïd Boukhris and Abdelaziz Souizi ∗
Laboratoire de Synthèse Organique et d’Agrochimie, Département de Chimie, Faculté des Sciences, Université Ibn Tofaïl,
B.P 133 Kénitra, Morocco
Received 23 January 2000; accepted 7 February 2000
Abstract
The nucleophilic ring opening of gem-dicyanoepoxides by LiBr or Li2NiBr4, in the presence of hydroxylamine
derivatives leads to new α-halo hydroxamic acids. These compounds has been used in the synthesis of α-
functionalized hydroxamic acids, α-hydroxy and α-amino acids in good yields. © 2000 Published by Elsevier
Science Ltd. All rights reserved.
Although α-halo hydroxamic acids are well-known compounds, prepared from α-halo acids chlorides
and hydroxylamines,1,2 most of them are in the alkyl series, only a few are known in the aryl series,3 as
the accessibility of α-halo acids chlorides is not as easy.1,2 However, structurally diversified hydroxamic
acids are of considerable interest due to their potential biological activity as antibiotic antagonists,4 tumor
inhibitors,4 and metal chelators.5
We have shown that the reaction of epoxides 1 with hydrochlorides of hydroxylamines represents a
direct route to a number of α-chloro hydroxamic acids.6 Unfortunately, this method is useful only for α-
chloro hydroxamic acids. We therefore tried to find a more general method for the synthesis of α-bromo
hydroxamic acids. We report in this paper that α-bromo hydroxamic acids are less easily obtained from
epoxides 1, by using a lithium bromide.
Epoxides 1 (5 mmol) was dissolved in 15 mL of THF and 7.5 mmol of lithium bromide was added.
While the mixture was refluxed during 1 h, a solution of hydroxylamine hydrochlorides (10 mmol)
and triethylamine (10 mmol) in THF was added dropwise. After the addition was completed, refluxing
was continued for 1 h. The solvent was partially removed under reduced pressure and the residue was
extracted with dichloromethane. The combined extracts were dried (Na2SO4), filtered and evaporated
to afford the residual α-bromo hydroxamic acids 27 (Scheme 1, Table 1), which was chromatographed
over silica gel (hexane:ethyl acetate 3:2 as eluent) or recrystallized from benzene. Compound 2 gives a
positive red color test with ferric chloride.
The reaction was assumed to proceed by the association of the epoxides 1 with lithium bromide and
regioselective ring opening by the nucleophile Br− which always attacks the carbon β to the two nitrile
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00228-8
tetl 16508

2560
Scheme 1.
Table 1
Synthesis of α-bromo hydroxamic acids 2
groups. The unstable cyanohydrin loses lithium cyanide and the acyl cyanide intermediate reacts in situ
with the hydroxylamine derivative to afford α-bromo hydroxamic acids 2. When alcohols are used, the
reaction of epoxides 1 with lithium bromide allows a convenient access to α-bromoesters.8
The particular structure of α-halo amide derivatives gives these compounds interesting properties
which have been investigated.9–11 Among these properties, we have studied their ability to undergo
substitution reactions and the possibility to prepare α-lactams.10 The results suggested that the reaction
of α-halo hydroxamic acids 2 with nucleophiles might constitute a simple synthetic route to a number of
new hydroxamic acids. We now report our studies on this new reaction which proved to be a convenient
method of synthesis for α-functionalized hydroxamic acids 3 which, at the moment, is difficult to
access.12 In addition, a number of natural products have been isolated from bacterial cultures showing
marked inhibition of aminopeptidases. These products such as phebestin13 and probestin14 contain α-
hydroxy amide residues which are key units in their biological activity.
We have shown that α-alkoxy hydroxamic acids 37 can be obtained from α-halo hydroxamic acids
2, in a basic medium, not only alcohol but even water reacts as nucleophilic reagents so that α-hydroxy
hydroxamic acids 37 are also obtained according to this strategy (Scheme 2, Table 2, entries a–j).
Scheme 2.
We have shown that this reaction is not a direct nucleophilic substitution of the halogen but more likely
proceeds through the formation of an aziridinone intermediate 4 which then undergoes nucleophilic ring

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Table 2
Synthesis of α-alkoxy, α-hydroxy and α-amino hydroxamic acids 3
opening. Such an aziridinone intermediate was also postulated in order to explain the formation of α-
alkoxy hydrazides in the course of the reaction of α-halo hydrazides with alcohol in a basic medium.4
The same reaction was performed with amines as nucleophiles, at refluxing acetonitrile, to afford the
α-amino hydroxamic acids 37 in good to moderate yields (Table 2, entries k–r).
Scheme 3.
Table 3
Experimental conditions and physical data for α-hydroxy acids and α-amino acids 5
Hydrolysis of α-amino hydroxamic acids 3 gave the corresponding α-amino acids 5 (Y=N), which
are obtained in good yields when the reaction is run in a basic medium. This method was extended to
the synthesis of α-hydroxy acids 5 (Y=O) from α-hydroxy hydroxamic acids 3. In fact, employing 1N
NaOH in CH3CN or dioxan gave an essentially quantitative conversion of hydroxamic acids 3 into α-
hydroxy acids 5 or α-amino acids 5 (Scheme 3). Table 3 lists the α-amino and α-hydroxy acids 5 which
have been synthesized using this methodology.
In summary, we have described a new convenient one-pot synthesis of α-bromo hydroxamic acids. We
have also shown that the α-halo hydroxamic acids react in basic media to give aziridinone intermediates

2562
which can be trapped in the medium by nucleophiles present. The reaction opens a new route to α-alkoxy,
α-amino and α-hydroxy hydroxamic acids, which can give α-amino and α-hydroxy acids.
References
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7. Spectral data are in full agreement with the proposed structures. For example: 2a: IR (CCl4): ν 1720 (CO) and 3150–3400
1
(NH, OH) cm−1. H NMR (CDCl3, 250 MHz) δ ppm: 5.42 (s, 1H, CHBr); 7.65 (br s, 1H, OH); 7.31–7.47 (m, 5H, Ar,
NH); 2.29 (s, 3H, CH3). 13C NMR: 170.8 (dd, 2J=3.9 and 4.0 Hz, CO); 59.4 (d, 1J=154.2 Hz, CHBr); 127.0, 128.5, 129.8,
1
1
134.8 (Ar-ring C); 21.2 (q, J=126.2 Hz, CH3). Compound 2d: IR (Nujol): ν 1670 (CO) and 3120 (NH) cm−1. H NMR
(CDCl3+TFA, 250 MHz) δ ppm: 5.42 (s, 1H, CHBr); 7.30–7.40 (m, 4H, Ar); 3.78 (s, 3H, OCH3); 2.30 (s, 3H, CH3).
13C NMR: 166.8 (dd, 2J=4.0 and 4.4 Hz, CO); 58.8 (d, 1J=153.2 Hz, CHBr); 127.2, 128.8, 132.8, 139.4 (Ar-ring C); 21.2
(q, J=126.4 Hz, CH3); 64.5 (q, J=128.4 Hz, OCH3). HMRS calcd for C10H12NO2Br (M+·): 259.0865, found: 259.083.
1
1
Compound 2f: IR (Nujol): ν 1690 (CO) and 3125 (NH) cm−1. H NMR (CDCl3+TFA, 250 MHz) δ ppm: 5.44 (s, 1H,
1
CHBr); 7.35–7.45 (m, 5H, Ar); 3.77 (s, 3H, OCH3). 13C NMR: 166.6 (dd, J=4.1 and 4.2 Hz, CO); 58.4 (d, J=153.4
2
1
Hz, CHBr); 127.2, 128.8, 130.2, 135.4 (Ar-ring C); 64.4 (q, J=128.1 Hz, OCH3). HMRS calcd for C9H10NO2Br (M+·):
1
244.9865, found: 244.984; calcd for (M+−C2H4NO2): 170.9632; found: 170.961. Compound 3c: IR (CCl4): ν 1720 (CO)
and 3200–3400 (NH, OH) cm−1. 1H NMR (CDCl3, 250 MHz) δ ppm: 5.32 (s, 1H, CH); 7.61 (br s, 1H, OH); 7.31–7.41 (m,
5H, Ar, NH); 2.28 (s, 3H, CH3), 3.40 (s, 3H, OCH3). 13C NMR: 171.6 (s, CO); 58.3 (d, J=153.2 Hz, CH); 125.7, 128.5,
1
132.8, 138.4 (Ar-ring C); 20.2 (q, 1J=126.7 Hz, CH3), 57.3 (q, 1J=127.5 Hz, OCH3). Compound 3f: IR (CCl4): ν 1680 (CO)
and 3120 (NH) cm−1. H NMR (CDCl3, 250 MHz) δ ppm: 5.36 (s, 1H, CH); 7.30–7.42 (m, 5H, Ar, NH); 3.78 (s, 3H,
1
HNOCH3); 3.40 (s, 3H, OCH3); 2.30 (s, 3H, CH3). 13C NMR: 166.6 (dd, J=4.1 and 4.2 Hz, CO); 58.2 (d, J=153.5 Hz,
2
1
CH); 127.8, 129.2, 132.4, 139.7 (Ar-ring C); 21.2 (q, 1J=126.4 Hz, CH3); 57.4 (q, 1J=128.5 Hz, OCH3); 64.4 (q, 1J=128.5
Hz, HNOCH3). Compound 3g: IR (CCl4): ν 1720 (CO) and 3300–3400 (NH, OH) cm−1. H NMR (CDCl3, 250 MHz) δ
1
ppm: 5.35 (s, 1H, CH); 7.70 (br s,1H, OH); 7.31–7.41 (m, 5H, Ar, NH); 2.28 (s, 3H, CH3); 4.20 (s, 1H, OH). Compound 3p:
IR (CCl4): ν 1720 (CO) and 3210–3330 (NH, OH) cm−1. 1H NMR (CDCl3, 250 MHz) δ ppm: 5.03 (s, 1H, CH); 7.61 (br s,
1H, OH); 7.31–7.42 (m, 5H, Ar, NH); 2.52 (d, 3H, NCH3); 2.28 (s, 3H, CH3). 13C NMR: 169.5 (s, CO); 52.5 (d, 1J=152.6
Hz, CH); 127.8, 129.2, 132.4, 139.7 (Ar-ring C); 20.2 (q, 1J=126.7 Hz, CH3); 51.3 (q, 1J=126.5 Hz, NCH3). HMRS calcd
for C10H14N2O2 (M+·): 194.1055, found: 194.104. Compound 5g: IR (Nujol): ν 1720 (CO) and 3400 (OH) cm−1. 1H NMR
(CDCl3+TFA, 250 MHz) δ ppm: 5.36 (s, 1H, CH); 7.22 (m, 4H, Ar); 2.30 (s, 3H, CH3). HMRS calcd for C9H10O3 (M+·):
166.0629, found: 166.062. Anal. calcd: C, 65.06; H, 6.02. Found: C, 64.94; H, 5.98. Compound 5k: IR (Nujol): ν 15900
1
(CO), 2700 (NH) and 3060 (OH) cm−1. H NMR (CDCl3+TFA, 250 MHz) δ ppm: 5.31 (s, 1H, CH); 7.25–7.40 (m, 9H,
Ar); 2.30 (s, 3H, CH3). 13C NMR: 173.4 (s, CO); 58.9 (d, 1J=153.5 Hz, CH); 127.8, 129.2, 132.4, 139.7 (Ar-ring C); 21.2
1
(q, J=126.4 Hz, CH3). HMRS calcd for C15H15NO2 (M+·): 241.1103, found: 241.109. Anal. calcd: C, 74.69; H, 6.22; N,
5.81. Found: C, 74.37; H, 6.16; N, 5.77.
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