Microwave-assisted transformation of esters into hydroxamic acids

Article abstract of DOI:10.1055/s-2007-990803

A general, mild and efficient procedure with which to access hydroxamic acids, in good yields and purity, is reported. Esters are used as substrates and reacted with hydroxylamine, in the presence of a base, under microwave activation. The method has been

Full text of DOI:10.1055/s-2007-990803

PAPER
3201
Microwave-Assisted Transformation of Esters into Hydroxamic Acids
M
icrowave-Assist
s
e
d
Synthe
s
sis of
H
yd
u
roxamic
A
ci
n
ds ta Massaro,a Alessandro Mordini,*b Gianna Reginato,b Francesco Russo,b Maurizio Taddeic
a
ProtEra S.r.l., University Scientific Campus, Viale delle Idee 22, 50019 Sesto Fiorentino, Italy
ICCOM-CNR, Dipartimento di Chimica Organica ‘U. Schiff’, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
Fax +39(055)4573580; E-mail: alessandro.mordini@unifi.it
b
c
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy
Received 26 June 2007
tion, using hydroxylamine as a reagent, in the presence of
bases such as potassium hydroxide or sodium ethoxide.
Abstract: A general, mild and efficient procedure with which to ac-
cess hydroxamic acids, in good yields and purity, is reported. Esters
are used as substrates and reacted with hydroxylamine, in the pres-
ence of a base, under microwave activation. The method has been
successfully applied to enantiomerically pure esters without loss of
stereochemical integrity.
Since it is known that MW irradiation generally speeds up
slow reactions by simple, very efficient heating of the sys-
tem,23 we hoped to overcome the problems associated
with the long reaction times that are normally required for
the above transformation, in this way. To test our hypo-
thesis, we submitted an array of methyl esters to MW
irradiation, in the presence of hydroxylamine and
potassium hydroxide as base; the results are collected in
Table 1.
Key words: esters, chemoselectivity, hydroxamic acid, microwave
reactions, metalloproteinases
Hydroxamic acids are bidentate chelating agents that in-
teract with several zinc(II)-containing proteins. Mole-
cules containing this functional group behave as powerful
inhibitors of metalloproteinases1–4 and histone deacetyl-
ase,5–6 which are two important biological targets for anti-
cancer therapy. Moreover, the hydroxamic acid motif
occurs in other biomolecules such as naturally occurring
siderophores7,8 like pseudobactines, desferriooxamines,
ferrichromes and the fosmidomycin antibiotic9 and its
analogues10 which have been recovered and found to be
potent antimalarial agents.10–11
The data reported in Table 1 clearly show that the forma-
tion of hydroxamic acids from esters under MW irradia-
tion, occurs smoothly and is quite general; indeed it can be
performed on simple alkylaryl esters (entry 1), on both N-
protected (entries 2, 3, 5, 6) and unprotected (entry 4) ami-
no esters, on dipeptides (entries 7, 8), on protected hy-
droxyesters (entry 9) and on sulfonamido esters (entry
10), though in the latter case a partial decomposition of
the starting material was observed. Furthermore, it is
worthwhile noting that protective groups are also well tol-
erated under these reaction conditions. The tert-butoxy-
carbonyl (Boc) group for example, which can be lost
under MW irradiation in the presence of silica gel24 or
Lewis acids,25 remains intact under our reaction condi-
tions, though a partial deprotection was observed in the re-
action with Boc-proline ester (entry 5). Amidic bonds
(entries 7, 8) and ketals (entry 9) also survive without any
detectable decomposition. All the reactions went to com-
pletion in about six minutes, except in the case of the con-
version of Boc-protected phenylalanine methyl ester,
which required longer reaction times (12 min).
Due to its low stability, this hydroxamate moiety is usual-
ly introduced in the last step of the synthetic sequence
and, recently, several methods have been developed for
this purpose. So far, the most commonly used approaches
can be summarized as: reaction of O/N-protected hydrox-
ylamine with activated carboxylic acids,12–15 reaction of
esters with hydroxylamine,16,17 treatment of N-acyloxazo-
lidines with hydroxylamine in the presence of samarium
triflate,18 and coupling of carboxylic acids with hydroxy-
lamine in the presence of 2,4,6-trichloro[1,3,5]triazine19
or cyclic phosphonic anhydride (PPAA).20 However, a
general, mild and efficient procedure with which to access
hydroxamic acids, in good yields and purities, is still re-
quired.
Of particular interest is the dipeptide in entry 8, which has
been designed to be a new matrix metallo-protease
(MMP) inhibitor. Whilst substrate 1h, which has previ-
ously been obtained through a multistep synthesis,26 could
not be transformed into the desired hydroxamic acid
through usual methods (as mainly starting ester was re-
covered), MW irradiation led to the desired product 2h,
albeit in moderate yield.
Stemming from our interest in the development of new
metalloproteinase inhibitors,21,22 we have recently faced
the problem of transforming esters into the corresponding
hydroxamic acids at the end of multistep sequences with-
out loss of stereochemical integrity in the final product.
As a convenient methodology, we envisaged the use of
microwave (MW) activation in this simple transforma-
Yields of the MW-induced transformations were general-
ly good. All the final compounds gave a positive test for
hydroxamic acid by treatment with an iron(III) chloride
solution.27 The ester was consistently completely con-
sumed to give the hydroxamic acid as the major product,
sometimes accompanied by small amounts of the corre-
SYNTHESIS 2007, No. 20, pp 3201–3204
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x.
x
x
.
2
0
0
7
Advanced online publication: 21.09.2007
DOI: 10.1055/s-2007-990803; Art ID: Z15407SS
© Georg Thieme Verlag Stuttgart · New York

3202
A. Massaro et al.
PAPER
Table 1 Conversion of Esters into Hydroxamic Acids under Microwave Irradiation
Entrya
1
Ester
1a
Hydroxamic acid
Yield
71%
OMe
NHOH
O
O
2a
2b
NHBoc
NHBoc
NHOH
OMe
2
3
100%
70%
O
O
1b
NHBoc
OMe
NHBoc
NHOH
O
O
1c
2c
2d
2e
NH
NH
OMe
NHOH
4
5
88%
O
O
1d
1e
NBoc
NBoc
OMe
NHOH
50%b
O
O
NBoc
NBoc
6
7
O
OMe
50% b
O
NHOH
O
O
1f
2f
O
O
100%
OMe
NHOH
N
H
N
H
BocHN
O
NHBoc
O
1g
2g
NHOH
OMe
N
S
N
S
N
O
O
N
O
O
8
40%
O
O
2h
1h
O
O
9
O
OMe
O
NHOH
98%
O
O
1i
2i
O
O
O
O
S
OMe
S
NHOH
33%c
N
N
10
H
H
O
O
MeO
MeO
1k
2k
a All the reactions were carried out by irradiating the ester and hydroxylamine in MeOH, in the presence of base, for 6 min at 80 °C and 150 W.
b Protecting group was partially removed.
c Partial decomposition to 4-methoxyphenylsulfonic acid was observed.
Synthesis 2007, No. 20, 3201–3204 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Synthesis of Hydroxamic Acids
3203
Hydroxamic Acid Preparation; Typical Procedure
sponding carboxylic acid (entries 8, 9). Changing the base
used (potassium hydroxide or sodium ethoxide) did not
affect the outcome of the reaction; however, it must be
pointed out that the use of methanol as solvent was crucial
since alternative alcohols promoted initial transesterifica-
tion, which led to a decrease in the rate of hydroxamic
acid formation.
Methyl ester (0.2 mmol) was dissolved in anhydrous MeOH (0.5
mL) under nitrogen. The solution was charged with a preformed
slurry of hydroxylamine hydrochloride (44 mg, 0.6 mmol) and
KOH (71 mg, 1.2 mmol) in MeOH and the sealed flask was inserted
into the cavity of a Discovery Microwave System apparatus (CEM)
and heated for 6 min at 80 °C by microwave irradiation at 150 W
(the power level was previously allowed to settle).
The reaction mixture was acidified with 3 M HCl (or aq 25% AcOH
in the case of acid-sensitive compounds) to apparent pH 4. The re-
sulting solution was concentrated and the residue was dissolved in
a small amount of H2O and extracted several times with EtOAc until
TLC analysis of the aqueous phase revealed that no ferric chloride-
positive component remained.
With compounds 1a, 1b and 1d, a comparison between
classical heating (oil bath) and MW irradiation was car-
ried out and the results obtained (Table 2), clearly show
an improved performance of the MW-assisted process.
Table 2 Comparison of Reactions with and without MW Irradiation
The organic layer was dried over anhydrous Na2SO4 and the filtrate
was concentrated to give the desired hydroxamic acid, which was
purified by reverse phase HPLC (semipreparative column, Ultra-
sphere C-8, 5mm, 250 × 10 nm, flow rate 3.5 mL/min, MeCN–H20,
gradient containing 0.05% TFA).
Ester
Without MW irradiation
With MW irradiation
150 W, 80 °C, 6 min
25 °C, 4 h
49%
25 °C, 12 h
1a
1b
1d
15%
55%
71%
71%
100%
88%
N-Hydroxy-2-phenylacetamide (2a)19
Yield: 156 mg (71%); oil.
1H NMR (CD3OD, 200 MHz): d = 7.26–7.31 (m, 5 H), 3.44 (s, 2 H).
59%
64%
13C NMR (CD3OD, 50 MHz): d = 166.2, 136.2, 130.1, 129.2, 127.6,
Finally, we demonstrated that the use of MW irradiation
did not affect the stereochemical integrity of the chiral
compounds since the optical rotation of the hydroxamic
acid derivative of Boc-alanine methyl ester was found to
35.9.
(S)-N-(tert-Butoxycarbonyl)alanine Hydroxamate (2b)17
Yield: 200 mg (100%); oil; [a]D25 –29 (c 1, MeOH)
1H NMR (CD3OD, 400 MHz): d = 4.01 (q, J = 7.0 Hz, 1 H), 1.43 (s,
9 H), 1.28 (d, J = 7.2 Hz, 3 H).
13C NMR (CD3OD, 50 MHz): d = 169.9, 155.6, 78.1, 49.4, 28.5,
17.9.
be in agreement with the literature value {[a]20 –35 (c
D
0.8, MeOH); Lit.17 [a]20D –29 (c 1, MeOH)}. Likewise, in
the case of dipeptide 2g, only one diastereoisomer was ob-
1
served in the H NMR spectrum of the final hydroxamic
acid, confirming that no racemization had occurred during
the MW-induced reaction.
(S)-N-(tert-Butoxycarbonyl)phenylalanine Hydroxamate (2c)17
Yield: 280 mg (70%); oil.
In summary, we have shown that hydroxamic acids can be
easily prepared from the corresponding esters, through a
simple protocol, using hydroxylamine and a base under
microwave irradiation. The method is quite general,
shows a good tolerance for a range of functional groups,
and can be applied to enantiomerically pure amino esters
without any loss of stereochemical integrity.
1H NMR (CD3OD, 200 MHz): d = 7.34–7.23 (m, 5 H), 4.20 (m,
1 H), 3.05 (dd, J = 8.4, 13.6 Hz, 1 H), 2.85 (dd, J = 6.6, 13.6 Hz,
1 H), 1.39 (s, 9 H).
13C NMR (CD3OD, 50 MHz): d = 170.5, 157.0, 138.1, 130.1, 129.2,
127.4, 80.4, 55.1, 39.4, 28.6.
(S)-Proline Hydroxamate (2d)16
Yield: 166 mg (88%); oil.
1H NMR (D2O, 200 MHz): d = 4.31–4.22 (m, 1 H), 3.43–3.35 (m,
Starting materials were purchased from commercial sources and
used without further purification. Sulfonamide 1k was synthesized
according to the literature.28 Dipeptide N-Boc-Val-Phe-OMe (1g)
was prepared following typical peptide synthesis coupling proce-
dures.29 Dipeptide ester 1h was synthesized via a multistep se-
quence.26
2 H), 2.45–2.35 (m, 2 H), 2.20–2.0 (m, 2 H).
13C NMR (CD3OD, 50 MHz): d = 169.8, 59.4, 43.9, 26.3, 22.7.
(S)-N-(tert-Butoxycarbonyl)proline Hydroxamate (2e)19
Yield: 230 mg (50%); oil.
1H NMR (CD3OD, 200 MHz): d = 4.22–4.10 (m, 1 H), 3.60–3.40
Ethereal extracts were dried with Na2SO4. Reactions were moni-
tored by TLC using SiO2-coated plates; detection was accomplished
through staining with a KMnO4 basic solution. Flash column chro-
matography was performed using glass columns (10–50 mm wide)
and SiO2 (230–400 mesh). 1H NMR spectra were recorded at 200 or
400 MHz. For those compounds that are present as slowly intercon-
(m, 2 H), 2.0–1.80 (m, 4 H), 1.44 (s, 9 H).
13C NMR (CD3OD, 50 MHz): d = 169.9, 158.1, 79.8, 56.8, 43.9,
28.8, 26.4, 21.8.
(S)-tert-Butyl 4-(Hydroxycarbamoyl)-2,2-dimethyloxazolidine-
3-carboxylate (2f)30
Yield: 246 mg (50%); oil.
1H NMR (CD3OD, 200 MHz): d = 4.31–4.13 (m, 2 H), 4.0–3.88 (m,
1 H), 1.62 (s, 6 H), 1.42 (s, 9 H).
13C NMR (CD3OD, 50 MHz): d = 168.5, 152.4, 80.3, 66.4, 65.8,
62.4, 27.2, 23.1.
1
verting rotamers, H NMR experiments were performed at 50 °C
and signals of the averaged spectrum are reported when possible.
13C NMR spectra were recorded at 50 MHz. Chemical shifts were
determined relative to the residual solvent peak (MeOH, d = 3.31
ppm for 1H NMR; MeOH, d = 49.0 ppm for 13C NMR). Polarimetric
measurements were performed at l = 589 nm at the temperature
specified.
Synthesis 2007, No. 20, 3201–3204 © Thieme Stuttgart · New York

3204
A. Massaro et al.
PAPER
tert-Butyl (S)-1-[(S)-1-(Hydroxycarbamoyl)-2-phenylethyl-
carbamoyl]-2-methylpropylcarbamate (2g)
Yield: 80 mg (100%); colorless solid; mp 106–108 °C; [a]D
–44.34 (c 3.55, MeOH).
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25
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1H NMR (CD3OD, 400 MHz): d = 7.20–7.26 (m, 5 H), 4.55 (t,
J = 7.6 Hz, 1 H), 3.82 (d, J = 6.6 Hz, 1 H), 3.17–2.85 (m, 2 H),
1.98–1.83 (m, 1 H), 1.44 (s, 9 H), 0.83 (d, J = 6.8 Hz, 6 H).
13C NMR (CD3OD, 50 MHz): d = 173.9, 169.6, 157.9, 137.9, 130.1,
129.2, 127.5, 80.6, 61.7, 53.5, 38.8, 31.9, 28.7, 19.6, 18.6.
Anal. Calcd for C19H29N3O5: C, 60.14; H, 7.70; N, 11.07. Found: C,
60.51; H, 7.36; N, 11.21.
(S)-1-[(S)-3-Benzylsulfanyl-2-(furan-2-ylmethylisobutylami-
no)propionyl]piperidine-2-carboxylic Acid Hydroxyamide (2h)
Yield: 60 mg (40%); oil; [a]D25 +68.53 (c 0.35, MeOH).
1H NMR (CD3OD, 400 MHz): d = 7.42 (m, 1 H), 7.29–7.20 (m,
5 H), 6.33 (dd, J = 2.0, 3.2 Hz, 1 H), 6.15 (d, J = 3.2 Hz, 1 H), 5.33
(m, 1 H), 3.73 (s, 2 H), 3.72–3.45 (m, 3 H), 3.35–2.91 (m, 3 H),
2.89–2.60 (m, 1 H), 2.35–2.10 (m, 3 H), 1.68–1.46 (m, 6 H), 0.80
(s, 3 H), 0.78 (s, 3 H).
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13C NMR (CD3OD, 50 MHz): d = 173.2, 170.5, 154.2, 143.2, 140.3,
130.1, 129.6, 128.0, 111.3, 109.9, 62.8, 59.7, 51.8, 44.0, 42.4, 38.0,
27.9, 27.8, 27.5, 26.3, 21.1, 20.9, 20.8.
Anal. Calcd for C25H35N3O4S: C, 63.4; H, 7.45; N, 8.87. Found: C,
63.51; H, 7.41; N, 8.83.
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(S)-N-Hydroxy-2,2-dimethyl-1,3-dioxolane-4-carboxamide (2i)
Yield: 160 mg (98%); oil; [a]D25 +22.22 (c 1.44, MeOH).
1H NMR (CD3OD, 400 MHz): d = 4.57 (dd, J = 7.4, 5.4 Hz, 1 H),
4.25 (dd, J = 8.4, 7.4 Hz, 1 H), 4.04 (dd, J = 8.4, 5.4 Hz, 1 H), 1.46
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N-Hydroxy-2-(4-methoxyphenylsulfonyl)acetamide (2k)31
Yield: 260 mg (33%); oil.
1H NMR (CD3OD, 200 MHz): d = 7.78 (d, J = 8.8 Hz, 2 H), 7.06 (d,
J = 8.8 Hz, 2 H), 3.86 (s, 3 H), 3.48 (s, 2 H).
13C NMR (CD3OD, 50 MHz): d = 167.7, 164.5, 132.3, 130.2, 115.3,
56.2, 44.5.
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Acknowledgment
We thank Julie Colombel for her contribution in running some of
the MW-induced reactions.
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Synthesis 2007, No. 20, 3201–3204 © Thieme Stuttgart · New York