Synthesis of hydroxamic acids by activation of carboxylic acids with N,N'-carbonyldiimidazole: Exploring the efficiency of the method

Article abstract of DOI:10.1080/00397910903026723

Activation of carboxylic acids with N,N'-carbonyldiimidazole followed by the reaction with anhydrous or aqueous hydroxylamine hydrochloride was demonstrated to be an operationally simple method for the synthesis of hydroxamic acids in good yield and high purity after aqueous workup. The potential by-product, N,O-diacylhydroxylamine, is cleanly transformed to hydroxamic acid in these reaction conditions.

Full text of DOI:10.1080/00397910903026723

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Synthesis of Hydroxamic Acids by
Activation of Carboxylic Acids with N,N′-
Carbonyldiimidazole: Exploring the
Efficiency of the Method
Natalija Usachova a , Gundars Leitis a , Aigars Jirgensons a & Ivars
Kalvinsh a
a Latvian Institute of Organic Synthesis, Riga, Latvia
Version of record first published: 22 Feb 2010
To cite this article: Natalija Usachova, Gundars Leitis, Aigars Jirgensons & Ivars Kalvinsh (2010):
Synthesis of Hydroxamic Acids by Activation of Carboxylic Acids with N,N′-Carbonyldiimidazole:
Exploring the Efficiency of the Method, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:6, 927-935
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Synthetic Communications1, 40: 927–935, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903026723
SYNTHESIS OF HYDROXAMIC ACIDS BY ACTIVATION
OF CARBOXYLIC ACIDS WITH N,N0-
CARBONYLDIIMIDAZOLE: EXPLORING THE
EFFICIENCY OF THE METHOD
Natalija Usachova, Gundars Leitis, Aigars Jirgensons, and
Ivars Kalvinsh
Latvian Institute of Organic Synthesis, Riga, Latvia
Activation of carboxylic acids with N,N0-carbonyldiimidazole followed by the reaction with
anhydrous or aqueous hydroxylamine hydrochloride was demonstrated to be an operation-
ally simple method for the synthesis of hydroxamic acids in good yield and high purity after
aqueous workup. The potential by-product, N,O-diacylhydroxylamine, is cleanly trans-
formed to hydroxamic acid in these reaction conditions.
Keywords: Activation; N,N-carbonyldiimidazole; carboxylic acid; hydroxamic acid; hydroxylamine
Hydroxamic acid provides central functionality in a number of metalloproteinase
inhibitors because of its ability to strongly coordinate with metal ions and as such
has high relevance for the development of new pharmaceuticals.[1] Common methods
of hydroxamic acid synthesis are the reaction of ester with hydroxylamine[2] or the
activation of carboxylic acid followed by the reaction with O-protected, N,O-
protected, or unprotected hydroxylamine.[3,4] Coupling of carboxylic acids with pro-
tected hydroxylamines is very often used despite the facts that these are relatively
expensive reagents and an additional deprotection step is necessary to complete
the synthesis. The reason for this is that there are drawbacks associated with com-
petitive N,O-diacylation of unprotected hydroxylamine and difficulties in obtaining
the product in pure form.
As a part of drug discovery program, we required a method for parallel
synthesis of hydroxamic acids from carboxylic acids that provided the products in
high purity without chromatographic purification or crystallization. We turned
our attention to the activation of carboxylic acids with N,N0-carbonyldiimidazole
(CDI), a well-known approach for the synthesis of carboxylic acid derivatives. It is
attractive because of the simple separation of products from water-soluble by-
products.[5] A literature search reveled surprisingly scant information regarding
the use of unprotected hydroxylamine as a reaction partner for CDI-activated
Received April 7, 2009.
Address correspondence to Aigars Jirgensons, Latvian Institute of Organic Synthesis, Riga,
LV-1006, Latvia. E-mail: aigars@osi.lv
927

928
N. USACHOVA ET AL.
Scheme 1. Activation of carboxylic acid and the reaction with formed hydroxylamine in situ.
carboxylic acid. In early work, Staab et al. demonstrated the preparation of two sim-
ple hydroxamic acids from CDI-activated carboxylic acids and hydroxylamine
hydrochloride.[6] No additional base was necessary because imidazole liberated
during the reaction promoted deprotonation of hydroxylamine hydrochloride
(Scheme 1). We were able to locate just a few other examples of this approach in
the literature[7] and decided that additional investigation would be necessary to
explore the efficiency of this method.[8]
Carboxylic acid 1a was used as a test substrate to find the best reactant ratio
for hydroxamic acid 3a synthesis (Scheme 2, Table 1). The high-performance liquid
chromatography (HPLC) purity and yield were determined after extractive workup.
The best results can be achieved using slight excess of CDI over carboxylic acid and
in turn slight excess of hydroxylamine hydrochloride over CDI (Table 1, entry 4).
Care should be taken for the quality of CDI, which tends to decompose while stor-
ing. Typically, a reagent with >90% of CDI content (1H NMR) was used for the
experiments. When solid NH2OH ꢀ HCl was added to the solution of activated car-
boxylic acid, a heterogeneous reaction mixture has formed. It was established that
NH2OH ꢀ HCl can be added as an aqueous solution, leading to a homogeneous reac-
tion mixture, without significantly impairing yield and purity of the product 3a
(Table 2). This could be very useful for parallel synthesis, where the stock solutions
of the reagents are preferred.
Structurally different carboxylic acids 1b–i were transformed to the corre-
sponding carboxylic acids 3b–i at optimized conditions (Figure 1). Hydroxamic acids
3b–e were obtained from carboxylic acids 1b–e in excellent yield and high purity
(Table 3). Hydroxamic acids R- and S-3c were obtained from corresponding N-
Boc-protected phenylalanines R- and S-1c in high enantiomeric purity. Unsaturated
acids 1f and 1g gave hydroxamic acids 3f and 3g in somewhat reduced yield but
nevertheless high purity. Dihydroxamic acid 3h was obtained in poor yield because
Scheme 2. Synthesis of hydroxamic acid 3a from carboxylic acid using the CDI activation method.

SYNTHESIS OF HYDROXAMIC ACIDS
929
Table 1. Optimization of the reactant ratio with the test substrate 1a by adding solid
NH2OH ꢀ HCl to activated carboxylic acid
Entry
CDI (eq)
Solid NH2OH ꢀ HCl (eq)
Yield (%)
HPLC purity (%)
1
2
3
4
1
1.5
1
100
87
90
35
98
98
1.5
1.5
1.5
1.5
2
82
96
Table 2. Yield and purity of hydroxamic acid 3a by adding aqueous NH2OH ꢀ HCl
to activated carboxylic acid
Aq. NH2OH ꢀ HCl
Entry
CDI (eq)
Eq
M
Yield (%)
HPLC purity (%)
1
2
3
4
1.5
1.5
1.5
1.5
4
2
4
2
4
2
2
4
86
94
87
85
99
98
99
99
Figure 1. Carboxylic acids 1b–i and the corresponding hydroxamic acids 3b–i.

930
N. USACHOVA ET AL.
Table 3. Transformation of carboxylic acids 1b–i to hydroxamic acids 3b–i
Entry
Hydroxamic acid
Methoda
Yield (%)
Purity (%)
1
3b
3b
A
B
93
88
99
99
75
84
66
70
52
60
23b
24
13
99 (HPLC)
97 (HPLC)
2
4
R-3c
S-3c
3d
A
A
A
A
A
B
93 (HPLC), ee 93
>90 (1H NMR), ee 93
95 (HPLC)
>85 (1H NMR, EA)
95 (LC=MS)
93 (LC=MS)
5
6
7
3e
3f
8
9
3f
3g
10
11
12
13
14
A
B
90 (LC=MS)
84 (LC=MS)
>90 (1H NMR)
82 (LC=MS)
27 (LC=MS)
3g
3h
A
A
B
3i
3i
aMethod A: addition of solid NH2OH ꢀ HCl; method B: addition of aqueous 2 M NH2OH ꢀ HCl (2 eq)
after activation of carboxylic acid.
bCrystallized from water.
of its high water solubility, making extractive workup unproductive. Very poor yield
of hydroxamic acid 3i was obtained from propiolic acid (1i), likely due to the
incompatibility of the conjugated triple bond with reaction conditions.
Because we were aware of potential N,O-diacylhydroxylamine formation in
given reaction conditions, an experiment was done where carboxylic acid 1a was acti-
vated with CDI and then subjected to the reaction with hydroxamic acid 3a
1
(Scheme 3). According to H NMR spectra of the crude product, this led to almost
quantitative formation of N,O-diacylhydroxylamine 5, which was obtained in good
isolated yield. However, the product of diacylation 5 cleanly converted to hydroxa-
mic acid 3a in the reaction with hydroxylamine hydrochloride and imidazole as a
base. This indicated that N,O-diacylhydroxylamine likely forms as an intermediate
or a by-product; however, it acylates hydroxylamine to give the required hydroxamic
acid 3.
In summary, we have demonstrated that activation of carboxylic acids with
CDI followed by the reaction with anhydrous or aqueous hydroxylamine hydro-
chloride is an operationally simple method to obtain structurally different hydrox-
amic acids in high purity and is a method of choice for parallel synthesis. It was
Scheme 3. Synthesis of N,O-diacylhydroxylamine 5 and its reaction with hydroxylamine.

SYNTHESIS OF HYDROXAMIC ACIDS
931
shown that potential by-product N,O-diacylhydroxylamine is cleanly transformed to
hydroxamic acid in these reaction conditions.
EXPERIMENTAL
Reagents and starting materials were obtained from commercial sources and
used as received. The solvents were purified and dried by standard procedures prior
to use. All reactions were performed under an argon atmosphere. Thin-layer chro-
matography (TLC) was performed on silica gel and was visualized by staining with
KMnO4. NMR spectra were recorded on a Varian Mercury spectrometer (200 MHz)
with chemical shifts values (d) in parts per million (ppm) relative to tetramethylsilane
(TMS) using residual chloroform signal as internal standard. HPLC analysis was
performed on SymmetryShield RP18, 5 mm, 4.6 ꢁ 150 mm, on Apollo C18 (5 M),
4.6 ꢁ 150-mm column, mobile phase MeCN–0.1% aq. H3PO4, gradient 15 min,
5=95–95=5%, flow rate 1 ml=min, column temperature 40 ꢂC, detection UV-210 at
254 nm. Chiral HPLC was performed on Chiralpack IA, 4.6 ꢁ 250-mm mobile phase
100% isopropylalcohol (IPA), isocratic, flow rate 0.2 ml=min. LC=MS analysis was
performed using Micromass Quatro MicroTM AP Phenomenex, Gemini 5u C18
11OA, 50 ꢁ 2 mm, 5 mm, mobile phase MeCN (0.1% aq. HCOOH)–H2O (0.1%
HCOOH). Optical rotations were measured on a Perkin-Elmer 141 polarimeter.
General Procedures for the Synthesis of Hydroxamic Acids 1
Procedure A. CDI (4.5 mmol, 1.5 eq) was added to a solution of carboxylic
acid 1 (3.0 mmol) in dry tetrahydrofuran (THF) (5 ml). The reaction mixture was
stirred for 1 h. Powdered hydroxylamine hydrochloride (417 mg, 6 mmol) was added.
The resulting mixture was stirred overnight (ca. 16 h). The mixture was diluted with
5% aq. KHSO4 (30 ml) and extracted with EtOAc (2 ꢁ 30 ml). The combined organic
phase was washed with brine (30 ml) and dried over Na2SO4. The extract was filtered
and concentrated in vacuo to give the product 3.
Procedure B. This was analogous to procedure A, but 2M aqueous hydroxy-
lamine hydrochloride (3 mL, 6 mmol) was used instead of solid hydroxylamine
hydrochloride.
N-Hydroxy-2-o-tolylacetamide (3a)
According to method A: 476 mg (96%). Colorless crystals, mp 157 ꢂC. HPLC
purity (UV 210 nm). According to method B: 466 mg (99%). Colorless crystals, mp
151 ꢂC. HPLC purity 99% (UV 210 nm). MS: 166 (M þ 1).1H NMR (DMSO-d6) d:
2.25 (3H, s, CH3), 3.28 (2H, s, partially overlapped with H2O, CH2), 7.0–7.2 (4H,
m, Ar), 8.78 (1H, s, NH) and 10.59 ppm (1H, s, OH).
N-Hydroxy-3-(4-methoxyphenyl)propanamide (3b)[9]
According to method A: 545 mg (93%). Colorless crystals, mp 114 ꢂC (lit.
113–115 ꢂC). HPLC purity 99% (UV 210 nm). According to method B: 515 mg

932
N. USACHOVA ET AL.
(88%). Colorless crystals, mp 110 ꢂC. HPLC purity 98% (UV 210 nm). MS: 196
1
(M þ 1). H NMR (DMSO-d6) d: 2.18 (2H, t, J ¼ 7.8 and 15.6 Hz, 3-CH2), 2.71
(2H, t, J ¼ 7.8 and 15.6 Hz, 2-CH2), 3.69 (3H, s, CH3), 6.80 (2H, d, J ¼ 8.8 Hz,
30,50-CH), 7.08 (2H, d, J ¼ 8.8 Hz, 20,60-CH), 8.67 (1H, s, NH) and 10.32 ppm (1H,
s, OH).
(S)-N-Hydroxy-2-t-butoxycarbonylamino-3-phenylpropanamide
(S-3c)[4d]
According to method A: Colorless crystals 902 mg (ꢃ100%), mp > 132 ꢂC (dec.),
20
HPLC purity 93% (UV 210 nm), chiral HPLC ee 92%, ½aꢄD ¼ þ8.7o (c 1, EtOH, 25 ꢂC)
20
1
(lit. ½aꢄD ¼ þ25.2o (c 1, EtOH), MS: 281 (M þ 1). H NMR (DMSO-d6) d: 1.1–1.4
(9H, m, CH3), 2.6–2.9 (2H, m, CH2), 4.00 (1H, dd, J ¼ 8.8 and 13.7 Hz, CH), 6.97
(1H, d, J ¼ 8.8 Hz, carbamate NH), 7.1–7.4 (5H, m, Ar), 8.83 (1H, s, hydroxamic acid
NH) and 10.60 ppm (1H, s, OH). Note: A notable difference in optical rotation value
compared to that reported in the literature was observed.
(R)-N-Hydroxy-2-t-butoxycarbonylamino-3-phenylpropanamide
(R-3c)
According to method A: 911 mg (ꢃ100%). Colorless crystals, mp > 138 ꢂC
20
(dec), HPLC purity 98% (UV 210 nm), chiral HPLC ee 92%, ½aꢄD ¼ ꢅ9.7o (c 1,
1
EtOH, 25 ꢂC) MS: 281 (M þ 1). H NMR identical to the compound S-3c.
N-Hydroxybenzamide (3d)[10]
According to method A: 307 mg (75%). Pale yellow crystals, mp 113 ꢂC
(>140 ꢂC dec) (lit. 126–127 ꢂC), HPLC 89% (UV 210 nm), MS: 138.1 (M þ 1).
1H NMR (DMSO-d6) d: 7.3–7.6 (3H, m, 30,50-CH and 40-CH), 7.72 (1.5H, d,
J ¼ 7.8 Hz, 20,60-CH, tautomer), 7.92 (0.5H, d, J ¼ 7.81 Hz, 20,60-CH tautomer),
9.02 (1H, s, NH) and 11.18 ppm (1H, s, OH).
N-Hydroxyadamantane-1-carboxamide (3e)[11]
According to method A: 581 mg (99%). Pale yellow crystals, mp 141 ꢂC
(>145 ꢂC dec.) (lit. > 149 ꢂC dec). 1H NMR (DMSO-d6) d: 1.62 (6H, s,
4,6,10-CH2), 1.73 (6H, s, 2,8,9-CH2), 1.92 (3H, s, 3,5,7-CH), 8.48 (1H, s, NH),
and 10.21 (1H, s, OH). Anal. calcd. for C11H17NO2–C11H16O2, (6:1): C, 68.4%; H,
8.8%; N, 6.2%. Found: C, 68.3%, H, 9.0%; N, 6.2%.
(E)-N-Hydroxy-3-phenylacrylamide (3f)[12]
According to method A: 321 mg (66%) pale pink crystals, mp 109 ꢂC (>115 ꢂC
dec) (lit. 114–115 ꢂC), LC=MS purity 96% (UV 210 nm). According to method B:
pale pink crystals, 340 mg (70%), mp 107 ꢂC (>115 ꢂC dec), LC-MS purity 93%
1
(UV 210 nm), MS: 164 (M þ 1). H NMR (DMSO-d6) d: 6.44 (1 H, d, J ¼ 16.1 Hz,

SYNTHESIS OF HYDROXAMIC ACIDS
933
2-CH), 7.3–7.6 (5H, m, Ar), 7.44 (1H, d, J ¼ 16.1 Hz, 3-CH), 9.04 (1H, s, NH) and
10.75 ppm (1H, s, OH).
N-Hydroxy-2E,4E-hexa-2,4-dienoic Acid Amide (3g)[4c]
According to method A: 208 mg (54%). Pale yellow crystals, mp 118 ꢂC (dec),
LC=MS purity 85% (UV 210 nm). According to method B: 227 mg (60%) Pale yellow
crystals, mp 120 ꢂC (>130 ꢂC dec), LC=MS purity 85% (UV 210 nm), MS: 128
(M þ 1). 1H NMR (DMSO-d6) d: 1.77 (3H, d, J ¼ 5.1 Hz, CH3), 5.72 (1H, d,
J ¼ 15.4 Hz, 2-CH), 5.9–6.4 (2H, m, 4-CH un 5-CH), 7.00 (1H, dd, J ¼ 9.5 un
15.4 Hz, 3-CH), 8.87 (1H, s, NH) and 10.57 ppm (1H, s, OH).
N,N0-Dihidroxyoctanedioic Acid Diamide (3h)[12]
According to method A. When the reaction mixture was diluted with water a
precipitate formed that could not be taken in organic phase. The precipitate was col-
lected on a filter and dried in vacuo to give 143 mg (23%) as a colourless crystals with
m.p. > 160 ꢂC (dec.). 1H NMR (DMSO-D6) d: 1.19 (4H, broad s, 4,5-CH2); 1.44 (4H,
m, 3,6-CH2), 1.90 (4H, t, J ¼ 6.8 Hz, 2,7-CH2), 8.64 (2H, s, both NH) and 10.31 ppm
(2H, s, both OH).
N-Hydroxy-3-phenylpropynoic Acid Amide (3i)[10]
According to method A: 114 mg (24%), Brown oil. LC=MS purity 82% (UV
210 nm). According to method B: 65 mg (13%). Brown oil. LC=MS purity 27%
1
(UV 210 nm). MS: ¼162 (M þ 1) H NMR (DMSO-D6) d: 7.1–7.9 (5H, m, Ar);
9.33 (1H, s, NH) and 10.72 ppm (1H, s, OH).
2-o-Tolyl-N-(2-o-tolylacetoxy)acetamide (5)
CDI (730 mg, 4.5 mmol, 1.5 eq) was added to a solution of o-tolyl acetic acid
(1a) (450 mg, 3 mmol) in dry THF (6 ml), and the mixture was stirred at room tem-
perature for 3 h. N-Hydroxy-2-o-tolylacetamide (3a) was added to the mixture, and it
was stirred at room temperature for ca. 12 h. The mixture was diluted with 5% aq.
KHSO4 (30 ml) and extracted with EtOAc (2 ꢁ 30 ml). The combined organic phase
was washed with brine (2 ꢁ 30 ml), dried over Na2SO4, filtered, and evaporated. The
residue was recrystallized from MeCN to give N,O-diacylated hydroxylamine
(695 mg, (78%) as colorless crystals with mp 154 ꢂC and HPLC purity 99% (UV
210 nm). MS: 298 (M þ 1). Anal. calcd. for C18H19NO3: C, 72.7%; H, 6.4%; N,
4.7%. Found: C, 72.1%; H, 6.4%; N, 4.9%. 1H NMR (DMSO-d6) d: 2.24 (6H, s, both
CH3), 3.47 [2H, s, CH2C(¼O)], 3.83 [1H, s, CH2C(¼O)], 7.1–7.3 (8H, m, Ar) and
11.91 ppm (1H, s).
N-Hydroxy-2-o-tolylacetamide (3a) from N,O-Diacylhydroxylamine 5
Powdered NH2OH ꢁ HCl (76 mg, 1.1 mmol) and imidazole (75 mg, 1.1 mmol)
were added to the suspension of N,O-diacylhydroxylamine 5 (297 mg, 1 mmol) in

934
N. USACHOVA ET AL.
THF (3 ml). The mixture was stirred at room temperature for 12 h and diluted with
aqueous 5% KHSO4 (30 ml). The product was taken in EtOAc (2 ꢁ 30 ml), and
the combined organic phase washed with brine (30 ml) and dried over Na2SO4.
Filtration and evaporation gave compound 3a (268 mg, 81%). 1H NMR spectra were
identical to those of the compound prepared from carboxylic acid 1a.
ACKNOWLEDGMENT
Partial financial support from the European Regional Development Fund
(VPD1=ERAF=CFLA=05=APK=2.5.1=000029=014) is gratefully acknowledged.
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