A convenient method for the synthesis of N-hydroxyureas

Article abstract of DOI:10.1016/j.tetlet.2005.10.091

Treatment of amines with 1-(4-nitrophenol)-N-(O-benzylhydroxy)carbamate yields the O-benzyl protected N-hydroxyureas. Hydrogenation of the O-benzyl protected N-hydroxyureas over 5% Pd/BaSO₄ cleanly gives the N-hydroxyureas in good yield. In add

Full text of DOI:10.1016/j.tetlet.2005.10.091

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8841–8843
A convenient method for the synthesis of N-hydroxyureas
Dennis A. Parrish, Zhou Zou, C. Leigh Allen, Cynthia S. Day and S. Bruce King*
Department of Chemistry, Wake Forest University, Winston-Salem, NC 27109, USA
Received 10 August 2005; accepted 19 October 2005
Available online 7 November 2005
Abstract—Treatment of amines with 1-(4-nitrophenol)-N-(O-benzylhydroxy)carbamate yields the O-benzyl protected N-hydroxy-
ureas. Hydrogenation of the O-benzyl protected N-hydroxyureas over 5% Pd/BaSO4 cleanly gives the N-hydroxyureas in good yield.
In addition to primary and secondary aliphatic and aromatic amines, this method converts amino sugars to the corresponding
N-hydroxyureas without extensive protecting group chemistry.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The hydroxyurea functional group possesses metal-che-
lating and redox-properties allowing compounds con-
taining this group to interact with a variety of metallo
and redox-active proteins. N-Hydroxyureas act as inhib-
itors of various metal containing hydrolytic enzymes
including carboxypeptidase A,1 urease,2 and ribonucle-
ase3 and redox enzymes including lipoxygenase and
ribonucleotide reductase.4,5 The simplest member of this
class, N-hydroxyurea, currently finds clinical use as a
treatment for a variety of cancers and sickle cell dis-
ease.6,7 Oxidation of N-hydroxyurea, a non-substituted
N-hydroxyurea containing the –NHOH group, leads to
the formation of nitric oxide, (NO), an important bio-
logical second messenger that may play a role in the
activity of N-hydroxyurea.8 Our group initiated a pro-
ject for the synthesis and evaluation of carbohydrate-
derived N-hydroxyureas as potential site-specific NO
donors. The preparation of such compounds by tradi-
tional condensation of hydroxylamine with amino
sugar-derived isocyanates requires lengthy protection/
deprotection sequences.2,9 Using a previous method
for the synthesis of ureas as inspiration,10 we wish to
report a convenient two-step procedure for the conver-
sion of amines, including unprotected amino sugars, to
the corresponding non-substituted N-hydroxyureas.
Scheme 1 depicts the general method for the conversion
of amines to N-hydroxyureas. Condensation of an
amine with 1-(4-nitrophenol)-N-(O-benzylhydroxy)car-
bamate, 1 in the presence of triethylamine yields the
O-benzyl protected N-hydroxyureas (2) in 84–98% yield
(Scheme 1).11 Addition of O-benzyl hydroxylamine to 4-
nitrophenyl chloroformate reproducibly forms 1 in 71%
yield.12 Hydrogenation (1 atm) of the O-benzyl pro-
tected hydroxyureas over 5% Pd/BaSO4 in MeOH/HCl
cleanly yields the desired N-hydroxyureas (Table 1).
Using Pd/C as the hydrogenation catalyst results in
the partial reduction of the N–O bond to give mixtures
H
H
N
O
N
NHRR'
O
O
+ NHRR'
O
O
NO2
2
1
H
H2, Pd/BaSO4
MeOH/HCl
N
NHRR'
HO
O
N-hydroxyureas
Scheme 1.
Keywords: N-Hydroxyureas; Nitric oxide; Nitric oxide donors; Carbohydrates; Hydrogenation.
*
Corresponding author. Tel.: +1 336 758 5774; fax: +1 336 758 4656; e-mail: kingsb@wfu.edu
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.091

8842
D. A. Parrish et al. / Tetrahedron Letters 46 (2005) 8841–8843
Table 1. Hydrogenation yields of O-benzyl protected N-hydroxyureas
using 5% Pd/BaSO4 in MeOH/HCl
O
NH2
O
HN
N
Entry
R, R0
Yield
100
O
H
HO
HO
O
1, MeOH, Et3N
H
HO
HO
1
n-Bu, H
50
H
OH
2Bn, H
OCH3
OH
OCH3
3
4
5
Ph, H
tBu, H
Et, Et
81
94
93
6
O
OH
HN
N
H2, Pd/BaSO4
MeOH
H
O
HO
HO
H
of N-hydroxyureas and ureas. This sequence converts
primary and second aliphatic amines (Table 1, entries
1, 2, 4, 5) and aromatic amines (Table 1, entry 3) to
the corresponding N-hydroxyureas. While the non-pro-
tected version of 1, 4-nitrophenol N-hydroxycarbamate,
provides direct access to a nucleotide-derived hydroxy-
urea following preparative HPLC,3 this reagent did
not yield reproducibly useful results in our experiments.
Control reactions show that this compound decomposes
in methylene chloride and triethylamine to carbon diox-
ide (as determined by headspace gas chromatography)
and 4-nitrophenol. In our hands the two-step procedure
using 1 appears more general for the preparation of
N-hydroxyureas.
OH
OCH3
7
Scheme 3.
Treatment of methyl 6-amino-6-deoxy-a-D-glucopyr-
anoside14 in MeOH with 1 yields the O-benzyl protected
N-hydroxyurea of methyl 6-amino-a-D-glucopyranoside
(6, Scheme 3) in 65% yield.15 Catalytic hydrogenation
over 5% Pd/BaSO4 of 6 yields the N-hydroxyurea
derived from methyl 6-amino-6-deoxy-a-D-glucopyrano-
side in 97% yield (7, Scheme 3).15 This sequence shows
that protection of the anomeric position as the methyl
glycoside prevents the observed cyclization/dehydration
sequence and allows the preparation of stable, highly
functionalized carbohydrate-derived N-hydroxyureas.
In summary, this two-step procedure provides a direct,
convenient, and alternative method for the preparation
of non-substituted N-hydroxyureas from the condensa-
tions of hydroxylamines with isocyanates or other car-
bamates.16 This preparation of carbohydrate-derived
N-hydroxyureas indicates this method will be quite use-
ful for the synthesis of highly functionalized N-hydroxy-
ureas using minimal functional group protection.
Condensation of a suspension of D-1-amino-1-deoxy
fructose hydrochloride13 in MeOH with 1 yields the
O-benzyl protected N-hydroxyurea of 1-amino fructose
(3, Scheme 2) in 76% yield. This result demonstrates
the ability of 1 to selectively react with amines relative
to alcohols, allowing the formation of carbohydrate-
derived N-hydroxyureas without alcohol protection.
Hydrogenation of 3 initially produces the hydroxyurea
(4, Scheme 2) but NMR spectroscopy clearly shows this
compound undergoes rearrangement to another species.
X-ray crystallography identifies this new compound as
the cyclic hydroxyurea (5, Scheme 2) that likely arises
from a condensation of the N-hydroxyurea nitrogen
atom on the keto form of the carbohydrate to give a
five-membered ring that dehydrates to 5 (Scheme 2).
Exposure of D-glucosamine to the same sequence simi-
larly gives a stable O-benzyl protected N-hydroxyurea
that rearranges to the corresponding cyclic hydroxyurea
upon deprotection.
Acknowledgments
This work was supported by the National Institutes of
Health (HL62198, SBK) and the Department of Defense
(DAMD17-01-1-0664, SBK). The NMR spectrometers
used in this work were purchased with partial support
from NSF (CHE-9708077) and the North Carolina Bio-
technology Center (9703-IDG-1007).
OH
H
H
OH
N
N
O
1, MeOH, Et3N
O
NH3
O
Cl
HO
HO
OH
HO
O
HO
OH
HO
3
O
OH
H
H
H
N
H
H2, Pd/BaSO4
MeOH
N
N
N
OH
O
OH
OH
HO
HO
OH
OH
HO
O
O
4
O
O
HO HON
HO HON
Cyclization
- H2O
NH
NH
HO
HO
OH
OH OH
OH OH
5
Scheme 2.

D. A. Parrish et al. / Tetrahedron Letters 46 (2005) 8841–8843
8843
addition of pyridine (2.00 mL, 24.99 mmol) under an
argon atmosphere. The reaction flask was cooled to 0 ꢁC
and 4-nitrophenyl chloroformate (4.200 g, 20.82 mmol)
was added. A reflux condenser was attached, and the
reaction mixture was heated at reflux for 24 h. Upon
cooling, the homogeneous organic solution was washed
with 1 M NaHCO3 (3 · 40 mL) and H2O (40 mL). The
organic fraction was dried with MgSO4, filtered, and
concentrated until solid material began to precipitate. A
chloroform–hexane mixture (5:6, 22 mL) was added. The
resulting solid was collected by vacuum filtration, washed
with the chloroform–hexane mixture until all yellow
discoloration was removed, and dried to give 1 (4.25 g,
71%) as a white solid; Rf 0.78 (1:1 EtOAc/hexanes); mp
131–133 ꢁC; 1H NMR (CDCl3) d 8.20 (d, 2H), 7.82
(s, 1H), 7.40–7.34 (m 5H), 7.26 (d, 2H), 4.92 (s, 2H); 13C
NMR (CDCl3) d 155.0, 153.7, 145.1, 134.7, 129.2, 128.9,
128.7, 125.2, 121.9, 79.0.
References and notes
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1
15. For 6: Rf 0.25 (4:1 CH2Cl2/CH3OH); H NMR (CD3OD,
300 MHz) d 7.39–7.28 (m, 5H), 4.75 (s, 2H), 4.61 (d,
J = 3.75, 1H), 3.55–3.47 (m, 2H), 3.35–3.26 (m, 3H), 3.31
(s, 3H), 3.07 (t, J = 9.3Hz, 1H); 13C NMR (D2O, 75 MHz)
d 163.2, 137.8, 130.6, 129.9, 101.7, 79.9, 75.1, 74.0, 73.6,
72.1, 56.0, 42.0; LRMS (FAB) m/z 365 (M+Na)+; 377
(M+Cl)ꢀ; Anal. Calcd for C15H22N2O7Æ0.5 H2O: C, 51.28;
H, 6.60; N, 7.97; Found: C, 51.22; H, 6.36; N, 7.72. For 7:
Rf 0.22 (2:1 CH2Cl2/CH3OH); 1H NMR (D2O, 300 MHz)
d 4.61 (m, 1H), 3.58–3.42(m, 3H), 3.39–3.10 (m, 3H), 3.31
(s, 3H); 13C NMR (D2O, 75 MHz) d 163.8, 99.4, 73.3,
71.6, 71.5, 70.6, 55.2, 40.3; LRMS (FAB) m/z 275
(M+Na)+, 287 (M+Cl)ꢀ; Anal. Calcd for C8H16N2O7Æ0.5
H2O: C, 36.78; H, 6.56; N, 10.72. Found: C, 36.76; H,
6.93; N, 10.20.
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11. General procedure illustrated with n-butylamine. Carb-
amate 1 (0.976 g, 3.39 mmol) was added to a solution of
n-butylamine (0.335 mL, 3.39 mmol) and triethylamine
(0.472mL, 3.39 mmol) in methylene chloride (40 mL). The
reaction mixture was stirred until starting material was
consumed (as determined by TLC) and washed with 1 M
NaOH (3 · 30 mL), 1 M HCl (30 mL), and water (30 mL).
The organic fraction was dried with MgSO4, filtered, and
concentrated to give the O-benzyl protected N-hydroxy-
urea (0.737 g, 98%) as a white solid; Rf 0.40 (1:1 EtOAc/
hexanes); mp 46–48 ꢁC; 1H NMR (CDCl3) d 7.29 (m, 5H),
4.70 (s, 2H), 3.09 (t, 2H), 1.31 (m, 2H), 1.17 (m, 2H), 0.81
(t, 3H); 13C NMR (CDCl3) d 160.0, 135.5, 129.1, 128.7,
128.6, 78.5, 39.2, 31.8, 19.8, 13.6.
´
´
16. Opacˇic, N.; Barbaric, M.; Zorc, B.; Cetina, M.; Nagl, A.;
´
´
Frkovic, E.; Kralj, M.; Pavelic, K.; Balzarini, J.; Andrei,
´
´
G.; Snoeck, R.; De Clerq, E.; Raic-Malic, S.; Mintas, M.
J. Med. Chem. 2005, 48, 475–482, describes the recent
preparation of amino acid derived N-hydroxyureas using
benzotriazolecarbonyl amino acid amides.
12. 4-Nitrophenyl-N-(O-benzylhydroxy)carbamate
(1).
O-Benzyl hydroxylamine (2.565 g, 20.82 mmol) was dis-
solved in methylene chloride (70 mL) followed by the