Efficient conversion of O-substituted 3-hydroxy-4-imino-oxazolidin-2-ones into O-substituted α-hydroxyamidoximes

Article abstract of DOI:10.1021/ol040045v

(Chemical equation presented) An efficient and convenient two-step synthesis of O-substituted α-hydroxyamidoximes has been developed. The first step involves a high-yielding one-pot synthesis of the so far unknown O-substituted 3-hydroxy-4-imino-oxazolidin-2-ones by reacting cyanohydrins stepwise with 1,1′-carbonyldiimidazole and O-substituted hydroxylamines. The second step represents a novel, sodium methoxide-mediated conversion of O-substituted 3-hydroxy-4-imino-oxazolidin-2-ones into the corresponding O-substituted α-hydroxyamidoximes.

Full text of DOI:10.1021/ol040045v

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4403-4405
Efficient Conversion of O-Substituted
3-Hydroxy-4-imino-oxazolidin-2-ones into
O-Substituted
r-Hydroxyamidoximes
Thomas Kurz* and Khalid Widyan
Institute of Pharmacy, UniVersity of Hamburg, Bundesstrasse 45,
20146 Hamburg, Germany
kurz@chemie.uni.hamburg.de
Received July 7, 2004
ABSTRACT
An efficient and convenient two-step synthesis of O-substituted
yielding one-pot synthesis of the so far unknown O-substituted 3-hydroxy-4-imino-oxazolidin-2-ones by reacting cyanohydrins stepwise with
1,1 -carbonyldiimidazole and O-substituted hydroxylamines. The second step represents a novel, sodium methoxide-mediated conversion of
O-substituted 3-hydroxy-4-imino-oxazolidin-2-ones into the corresponding O-substituted -hydroxyamidoximes.
r-hydroxyamidoximes has been developed. The first step involves a high-
′
r
R-Hydroxyamidoximes are R-functionalized derivatives of
amidoximes, a class of compounds that has found applica-
tions in organic, analytical, and medicinal chemistry.
As a metal ion chelating functional group, the amidoxime
moiety represents a promising pharmacophore for the
development of metalloenzyme inhibitors.1 In analytical
chemistry, amidoximes are used as selective extracting
reagents for the quantitative spectrophotometric determina-
tion of toxic metal cations such as cadmium (II), vanadium
(V), and osmium (VIII).2 Amidoximes are versatile building
blocks for the synthesis of various heterocycles.1a,3 Further-
more, the ability of O-substituted amidoximes to act as
prodrugs of amidines has recently attracted considerable
attention in medicinal chemistry.4
have not been reported so far. Although the chemistry of
amidoximes has been studied intensively, relatively few
O-unsubstituted R-hydroxyamidoximes (I) are described in
the literature. Compounds I are only accessible by treatment
of cyanohydrins and R-hydroxyimidates with hydroxyl-
amine.5 However, due to the weaker nucleophilicity of
O-substituted hydroxylamines, these methods cannot be
applied for the synthesis of O-substituted R-hydroxyami-
doximes (II).
O-Alkyl(aralkyl)-substituted amidoximes are commonly
prepared by alkylation of hydroxyamidines with alkyl-
(aralkyl) halides and alkyl sulfates in the presence of a
suitable base.1a O-Aryl- and O-t-Bu-substituted amidoximes
Figure 1. R-Hydroxyamidoximes.
(1) (a) Eloy, F.; Lenaers, R. Chem. ReV. 1962, 62, 155. (b) Briggs, L.
K.; Cambie, R. C.; Dean, C.; Rutledge, P. S. Aust. J. Chem. 1976, 29, 327.
(2) (a) Chakravarty, S.; Deb, M. K.; Mishra, R. K. J. AOAC Int. 1993,
76 (3), 604. (b) Deb, M. K.; Mishra, N.; Patel, K. S.; Mishra, R. K. Analyst
1991, 116, 323.
(3) (a) Zinner, G. Perner, M., Gru¨nefeld, J., Schecker, H.-G. Arch. Pharm.
1986, 319, 1073. (b) Hussein, A. C. Heterocycles 1987, 26, 163.
(4) (a) Anbazhagan M., Boykin D. W, Stephens, C. E. Tetrahedron Lett.
2002, 43, 9089. (b) Clement, B. Drug Metab. ReV. 2002, 34, 565.
Only two O-substituted R-hydroxyamidoximes (II), which
have been prepared by treatment of R-hydroxyamidoximes
(5) (a) Tiemann, F. Chem. Ber. 1884, 17, 126. (b) Gross, F. Chem. Ber.
1885, 18, 1077. (c) Schiff, H. Liebigs Ann. Chem. 1902, 321, 357. (d)
Schwarz, G. Zur Cyclisierenden Carbonylierung von R-Hydroxycarbohy-
droximsa¨ureestern und N-Hydroxycarbamaten, Ph.D. Dissertation, Technical
University Carolo-Wilhelmina, Brunswick, Germany, 1987.
10.1021/ol040045v CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/28/2004

with trityl chloride in 40 and 60% yields, respectively, are
reported in the literature.6 In a previous publication we
described the synthesis and decarbonylation of O-substituted
3-hydroxyoxazolidin-2,4-diones as a novel synthetic pathway
for the preparation of O-protected R-hydroxy-hydroxamates.7
The lack of an efficient and general method for the
preparation of O-substituted R-hydroxyamidoximes prompted
us to investigate the synthesis and applicability of O-
substituted 3-hydroxy-4-imino-oxazolidin-2-ones as precur-
sors for the synthesis of the title compounds. So far,
O-substituted 3-hydroxy-4-imino-oxazolidin-2-ones (5) have
only been reported as intermediates but not isolated and
characterized.7
Compounds 5a-i have now been synthesized in a
convenient one-pot reaction by treatment of 1,1′-carbonyl-
diimidazole (CDI) with cyanohydrins (2),7,8 followed by
addition of O-substituted hydroxylamines to the CDI-
activated cyanohydrins (3) at room temperature in 86-91%
yield (Scheme 1, Table 1). During the reaction, the formation
Table 1. Synthesis of O-Substituted and O-Unsubstituted
3-Hydroxy-4-imino-oxazolidin-2-ones (5 and 6)
entry
R1
R2
yield
5a
5b
5c
5d
5e
5f
5g
5h
5i
PhCH2
Ph2CH
t-Bu
C3H5
t-Bu
Ph2CH
Ph2CH
Ph2CH
Ph2CH
PhCH2
Ph2CH
t-Bu
PhCH2
PhCH2
PhCH2
PhCH2
t-Bu
90%
86%
91%
90%
90%
90%
86%
87%
86%
92%
91%
95%
t-Bu
3,4-di-(CH3O)C6H3CH2
CH3
Ph
H
H
H
6a
6b
6c
(Scheme 2). Catalytic hydrogenation of 7a-c led to O-
unsubstituted R-hydroxyamidoximes 8a-c in 93-97% yield
(Scheme 2, Table 2).
Scheme 1
Scheme 2
In conclusion, we have developed an operationally simple
one-pot protocol for the preparation of previously unpub-
of intermediates 3 and 4 was monitored by IR spectroscopy.
The disappearance of the (CN) band in the IR spectra at 2231
cm-1 and the formation of two sharp absorption bands at
1695-1705 and 1795-1805 cm-1 clearly indicated the ring
closure of 4 to 5.
Table 2. Synthesis of O-Substituted and O-Unsubstituted
R-Hydroxyamidoximes (7 and 8)
Finally, catalytic hydrogenation of 5a-c afforded 3-hy-
droxy-4-imino-oxazolidin-2-ones (6a-c) in 92-95% yield.
Conversion of compounds 5a-i into O-alkyl-, O-aralkyl-,
and O-phenyl-substituted R-hydroxyamidoximes (7a-i) was
accomplished in high yields of 90-95% by refluxing 5a-i
in the presence of sodium methoxide (0.2 equiv) in methanol
for 1 h. When 6a was reacted with sodium methoxide (0.2
equiv), no decarbonylation occurred due to neutralization of
sodium methoxide by 6a. However, treatment of 6a with an
excess of sodium methoxide in methanol afforded 8a in 70%
entry
R1
R2
yield
7a
7b
7c
7d
7e
7f
7g
7h
7i
PhCH2
Ph2CH
t-Bu
C3H5
t-Bu
Ph2CH
Ph2CH
Ph2CH
Ph2CH
PhCH2
Ph2CH
t-Bu
PhCH2
PhCH2
PhCH2
PhCH2
t-Bu
95%
92%
91%
92%
90%
91%
90%
95%
90%
95%
93%
97%
t-Bu
3,4-di-(CH3O)C6H3CH2
CH3
Ph
H
H
H
8a
8b
8c
(6) Tronchet, J. M. J.; Zosimo-Landolfo, G. J. Carbohydr. Chem. 1986,
5, 631.
(7) Kurz, T.; Widyan, K. Org. Biomol. Chem. 2004, 2, 2023.
(8) Gassman, P. G.; Talley, J. J. Tetrahedron Lett. 1978, 40, 3773.
4404
Org. Lett., Vol. 6, No. 24, 2004

lished O-substituted 3-hydroxy-4-imino-oxazolidin-2-ones.
Their treatment with sodium methoxide (0.2 equiv) in
methanol furnished O-alkyl-, O-aralkyl-, and O-phenyl-
substituted R-hydroxyamidoximes in high yields. Further-
more, deprotection of O-benzyl-substituted R-hydroxyami-
doximes as well as decarbonylation of 3-hydroxy-4-imino-
oxazolidin-2-one 6a led to R-hydroxyamidoximes 8.
Acknowledgment. We thank Prof. Dr. D. Geffken for
his valuable help in the preparation of this manuscript.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, elemental analysis, and melting
points for compounds 5-8. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL040045V
Org. Lett., Vol. 6, No. 24, 2004
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