Microwave-assisted conversion of 4-nitrophenyl esters into 0-protected hydroxamic acids

Article abstract of DOI:10.1002/ejoc.200900201

The microwave-assisted synthesis of O-protected hydroxamic acids starting from 4-nitrophenyl esters and O-protected hydroxylamines is described. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009.

Full text of DOI:10.1002/ejoc.200900201

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900201
Microwave-Assisted Conversion of 4-Nitrophenyl Esters into O-Protected
Hydroxamic Acids
Thomas Kurz,*[a] Miriam K. Pein,[a] Linda Marek,[a] Christoph T. Behrendt,[a]
Lukas Spanier,[a] Krystina Kuna,[a] and Karin Brücher[a]
Keywords: Acylation / 4-Nitrophenyl esters / Hydroxamic acids / Microwave-assisted synthesis
The microwave-assisted synthesis of O-protected hy-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
droxamic acids starting from 4-nitrophenyl esters and O-pro- Germany, 2009)
tected hydroxylamines is described.
represents the introduction of the hydroxamate group at the
Introduction
end of a synthetic sequence by hydroxylaminolysis of unac-
tivated carboxylic esters.[1,7,8] In 2007 Massaro and co-
workers described the microwave-assisted transformation of
methyl esters into hydroxamic acids using hydroxylamine as
a nucleophile.[9] Recently, Woodward reported the micro-
wave-assisted, DABAL-Me3-catalyzed preparation of Wein-
reb amides starting from N,O-dimethyl hydroxylamine hy-
drochloride, sodium hydride and aliphatic esters.[10] Due to
their diprotic nature, the hydroxamate functionality is often
introduced into a molecule in an O-protected form during a
synthetic sequence.[1,8] Commonly O-protected hydroxamic
acids are prepared by reacting O-protected hydroxylamines
with reactive carboxylic acid derivatives (e.g. acid halides,
anhydrides) and by carbodiimide or 1,1Ј-carbonyldiimid-
azole mediated coupling reactions.[1] Furthermore, Giaco-
melli and co-workers reported the synthesis of O-protected
hydroxamic acids using 2-chloro-4,6-dimethoxy-1,3,5-tri-
azine as activating reagent.[11] However, in some cases the
activation step is only incomplete and the yields are poor.
The direct transformation of unactivated aliphatic esters
into O-Bn-protected hydroxamic acids using O-benzylhy-
droxylamine as a nucleophile has only been accomplished
in the presence of AlMe3 and LiHMDS, respectively.[12,13]
Several protecting groups with different characteristics are
currently used in hydroxamic acid chemistry. Among them,
the O-benzyl-group is one of the most important protecting
groups.[14] O-Benzylhydroxamates are readily deprotected
under mild reaction conditions in high yields by catalytic
hydrogenation on Pd-C. A structurally related group repre-
sents the O-1-naphthylmethyl group. Other common O-pro-
tecting groups are for instance the O-THP and the O-DMB
group.[15,16]
Due to the ability of hydroxamic acids to act as bidentate
chelating agents for a variety of different metal cations the
hydroxamate functionality represents a key pharmacophore
in the development of novel metalloenzyme inhibitors. Hy-
droxamic acids have been described as ACE-, PDF-,
HDAC-, MMP- and TACE-inhibitors.[1] Recently, the
introduction of the first HDAC-inhibitor Vorinostat
(Zolinza®) for the treatment of cutaneous T-cell lymphoma
has demonstrated the potential of hydroxamic acids in drug
design.[2] Besides Vorinostat, several hydroxamate-based an-
alogs are already in advanced clinical trials.[3] Naturally oc-
curring hydroxamic acids like the antibiotic Fosmidomycin
and various siderophores have as well attracted the interest
of organic and medicinal chemists.[4,5] Fosmidomycin is a
promising drug candidate for the treatment of malaria trop-
ica currently in phase 2 clinical trials (Figure 1).[6] In hetero-
cyclic chemistry α-functionalized hydroxamic acids have
found wide applications as building blocks for the prepara-
tion of different heterocycles.[7]
Figure 1. Vorinostat and Fosmidomycin.
Since their discovery by Lossen conventional, combina-
torial and microwave-assisted concepts have been developed
for the preparation of hydroxamic acids.[1] A common and
efficient strategy for the synthesis of free hydroxamic acids
[a] Institute of Pharmaceutical and Medicinal Chemistry,
Heinrich-Heine Universität Düsseldorf,
As not all synthetic problems can be solved using the
existing methods, novel protocols for the synthesis of hy-
droxamic acids are needed. In contrast to the microwave-
assisted preparation of free hydroxamic acids, the micro-
Universitätsstr. 1, 40225 Düsseldorf, Germany
E-mail: Thomas.Kurz@uni-duesseldorf.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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T. Kurz et al.
SHORT COMMUNICATION
wave-assisted synthesis of O-protected hydroxamates has trast to the smooth formation of O-arylmethyl-substituted
not been described before. We have now studied the micro- hydroxamic acids 3a–m, the O-THP-substituted analogs 3n
wave-assisted preparation of O-protected hydroxamic acids and 3o were obtained in only 39% and 41% yield respec-
by reacting 4-nitrophenyl esters with differently O-protected tively. The relatively low yields in case of compounds 3n
hydroxylamines. 4-Nitrophenyl esters are easily accessible, and 3o are most likely due to the partial deprotection of
less moisture sensitive than acid chlorides and storable at O-THP-protected hydroxamic acids 3n,o in the presence of
room temperature over a long period of time. To the best glacial acetic acid. The formation of the corresponding free
of our knowledge, 4-nitrophenyl esters have not been used hydroxamic acids as by-products during the microwave re-
for the preparation of O-protected hydroxamic acids so far. actions was confirmed by TLC analysis as well as by their
purple coloured reactions with ethanolic Fe(Cl)3 solution.
Treatment of compound 1g with O-THP-hydroxylamine
Results and Discussion
without glacial acetic acid as a catalyst provided the corre-
sponding O-THP protected hydroxamic acid 3o in 66%
yield.
4-Nitrophenyl esters 1a–g as well as four O-protected hy-
droxylamines 2a–d [O-benzyl(Bn)-hydroxylamine, O-1-
naphthylmethyl-hydroxylamine, O-3,4-dimethyloxybenzyl-
(DMB)-hydroxylamine and O-tetrahydropyranyl(THP)-hy-
droxylamine] have been prepared according to literature
procedures.[16–18] First we investigated the microwave-as-
sisted acylation of O-benzylhydroxylamine by 4-nitrophenyl
benzoate (1a) in microwave pressure tubes at 300 W
(Scheme 1). After several unsatisfactory attempts to synthe-
sise the expected N-(benzyloxy)amide 3a in presence of dif-
ferent bases (e.g. triethylamine and DMAP), we turned our
attention to glacial acetic acid as a catalyst. Interestingly,
the acid-catalysed reaction of 1a and O-benzylhydroxyl-
amine in dry toluene afforded the O-Bn-protected hy-
droxamic acid 3a in 86% yield after a reaction time of only
12 minutes. In contrast, the corresponding reaction of 1a
with O-benzylhydroxylamine in refluxing toluene provided
compound 3a in only 24% yield after 4 hours. The reaction
of both substrates in a sealed tube at 115 °C furnished
3a in 29% yield after 2 hours. When pentafluoro-
phenyl benzoate was used as an acylating agent instead of
4-nitrophenyl benzoate, the O-Bn-protected hydroxamic
acid 3a was obtained in 44% yield after 28 min under mi-
crowave irradiation. The aromatic and heteroaromatic 4-ni-
trophenyl ester analogs 1b and 1c provided the correspond-
ing O-Bn-protected hydroxamic acids 3b and 3c in yields of
72% and 87% after only 10 min at 300 W (Table 1). Finally,
The progress of all microwave reactions was monitored
by IR spectroscopy and TLC. The IR spectra showed the
disappearance of the ester C=O band of 1a–g at 1737–
1760 cm–1 as well as the formation of a new, sharp carbonyl
band of the hydroxamic acids (3a–o) at 1636–1676 cm–1. A
simple work up procedure followed by recrystallisation
from appropriate solvents or chromatographic purification
furnished compounds 3a–o as analytically pure products.
The structures of all novel compounds were elucidated by
1H NMR, 13C NMR, IR spectroscopy and elemental analy-
sis (see Exp. Section).
Conclusions
In conclusion, we have developed an efficient, fast and
convenient method for the microwave-assisted synthesis of
various O-protected hydroxamic acids starting from reac-
tive 4-nitrophenyl esters and differently O-protected hy-
droxylamines.
Experimental Section
General: Melting points: Mettler FP 5, uncorrected values. IR: Var-
ian 800 FT-IR Scimitar series; KBr pellets unless otherwise stated.
NMR: Bruker Avance 500 (500 MHz for 1H; 125 MHz for 13C).
Cbz-protected 4-nitrophenyl ester 1d was also successfully Recorded in [D6]DMSO or CDCl3 using tetramethylsilane as an
internal standard. Elemental analysis: Perkin–Elmer PE 2400 CHN
elemental analyser instrument. Microwave-assisted synthesis: CEM
microwave model Discover.
converted into the corresponding Cbz-protected N-(ben-
zyloxy)amide 3d.
Microwave-Assisted Synthesis of Compounds 3a–o. General Pro-
cedure: 4-Nitrophenyl esters 1a–g (1 mmol) and the appropriate O-
protected hydroxylamine 2a–d (1.4 mmol) were dissolved in dry tol-
uene (2 mL) and added into a 10 mL glass pressure tube for micro-
wave-assisted reactions equipped with a magnetic stirrer bar. Two
drops of glacial acetic acid were added, before the tube was closed
with a silicon septum and the reaction mixture was subjected to
microwave irradiation for the indicated time (Table 1). The reaction
mixture was cooled to room temperature and transferred to a
round bottomed flask. The solvent was evaporated, ethyl acetate
(25 mL) was added and the mixture was washed subsequently with
citric acid solution (10%, 15 mL), a saturated, aqueous sodium car-
bonate solution (5ϫ10 mL) and water (10 mL). The organic layer
was dried with Na2SO4, filtered, and the solvent was evaporated.
The remaining residues were purified by crystallisation from appro-
Scheme 1. Microwave-assisted synthesis of O-protected hydroxamic
acids.
When O-benzylhydroxylamine was replaced by O-(1-
naphthylmethyl)hydroxylamine and O-3,4-DMB-hydroxyl-
amine, respectively, the corresponding O-substituted hy-
droxamic acids 3e–m were obtained in 49–94% yield after
10–20 min under microwave irradiation (Table 1). Finally,
we investigated the microwave-assisted acylation of O-THP-
hydroxylamine under similar reaction conditions. In con- priate solvents or by filtration through a short silica gel column
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Conversion of Nitrophenyl Esters into Hydroxamic Acids
Table 1. O-Protected hydroxamic acids 3a–o.
(3 cm) with ethyl acetate/n-hexane (3:7) as an eluent. Crystallisation
from ethyl acetate/n-hexane provided compounds 3a–o as analyti-
cally pure solids.
20 min (Table 1); temperature: 115 °C; pressure: 6 bar; PowerMax
cooling mode.
N-(Benzyloxy)naphthalene-1-carboxamide (3c): Colourless solid,
1
Parameters for the Microwave-Assisted Synthesis of Compounds 3a– yield 72% (200 mg), m.p. 122 °C. H NMR (500 MHz, CDCl3): δ
o: Discover mode; power: 300 W; ramp time: 1 min; hold time: 10–
= 5.12 (s, 2 H, CH2), 7.35–7.55 (m, 9 H), 7.82–7.86 (m, 1 H), 7.88–
Eur. J. Org. Chem. 2009, 2939–2942
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T. Kurz et al.
SHORT COMMUNICATION
7.92 (m, 1 H), 8.19–8.25 (m, 1 H), 8.44 (s, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 78.5, 124.5, 125.1, 125.3, 125.6, 126.6,
127.4, 128.3, 128.7, 128.9, 129.4, 130.3, 130.6, 131.3, 133.6, 135.2,
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7.20 (d, J = 3.43 Hz, 1 H), 7.36–7.37 (m, 1 H), 7.42–7.45 (m, 1 H),
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8.43 (d, J = 8.42 Hz, 1 H), 8.78 (s, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 77.2, 112.1, 115.7, 124.4, 125.1, 126.2, 126.9, 128.5,
[5]
[6]
129.0, 130.0, 130.7, 132.2, 133.8, 144.4, 145.7, 157.2 ppm. IR: ν
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1 H), 6.86 (d, J = 8.08 Hz, 1 H), 6.97 (d, J = 8.04 Hz, 1 H), 7.01
(s, 1 H), 7.19 (d, J = 3.28 Hz, 1 H), 7.41 (s, 1 H), 8.75 (s, 1 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 55.9, 78.8, 110.9, 112.1, 112.3,
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Received: February 26, 2009
N-[(Tetrahydropyran-2-yl)oxy]-2-phenylacetamide (3o): Colourless
solid, yield 39% (92 mg) (microwave-assisted), 66% (155 mg) (con-
ventional synthesis), m.p. 119 °C. 1H NMR (500 MHz, [D6]-
DMSO): δ = 1.47–1.72 (m, 6 H), 3.35 (s, 2 H), 3.50–3.55 (m, 1 H),
3.91–3.97 (m, 1 H), 4.83 (s, 1 H), 7.22–7.34 (m, 5 H), 11.25 (s, 1 H)
ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 18.6, 25.0, 28.1, 41.5,
61.7, 101.3, 126.8, 126.9, 128.6, 128.6, 129.3, 136.0, 167.3 ppm. IR:
ν = 1652 (C=O) cm–1. C H NO (235.29): calcd. C 66.36, H 7.28,
˜
13 17
3
N 5.95; found C 66.22, H 7.34, N 6.09.
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures, spectroscopic data, elemen-
tal analysis and melting points for compounds 3d–f,h,k,m.
Acknowledgments
Experimental support by Petra Stahlke, Gerrit Diederichs, David
Kudlek, Abdelaziz Mahkloufi and Christian Mühlenfeld is greatly
acknowledged.
Published Online: May 5, 2009
2942
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Eur. J. Org. Chem. 2009, 2939–2942