Oxidative cleavage of the C=N bond during singlet oxygenations of amidoximates

Article abstract of DOI:10.1016/S0040-4039(01)00887-5

Amidoximes are inert toward singlet oxygen (¹O₂), however, the photooxygenation of amidoximate anions proceeds smoothly and in high yield to give mixtures of amides and nitriles. The mechanism of these reactions appears to involve carbonyl oxide intermediates. The oxidative cleavage of amidoximates closely resembles the results obtained from nitric oxide synthase (NOS) oxidations of N-hydroxyarginine.

Full text of DOI:10.1016/S0040-4039(01)00887-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4765–4767
Oxidative cleavage of the CꢀN bond during singlet oxygenations
of amidoximates†
‡
8
Nu¨ket Ocal and Ihsan Erden*
San Francisco state University, Department of Chemistry and Biochemistry, 1600 Holloway Avenue, San Francisco,
CA 94132, USA
Received 28 February 2001; revised 2 April 2001; accepted 25 May 2001
Abstract—Amidoximes are inert toward singlet oxygen (1O2), however, the photooxygenation of amidoximate anions proceeds
smoothly and in high yield to give mixtures of amides and nitriles. The mechanism of these reactions appears to involve carbonyl
oxide intermediates. The oxidative cleavage of amidoximates closely resembles the results obtained from nitric oxide synthase
(NOS) oxidations of N-hydroxyarginine. © 2001 Elsevier Science Ltd. All rights reserved.
The oxidation of N-hydroxyarginine by the nitric oxide
synthase (NOS) to citrulline and nitric oxide (NO) is an
important biological process since nitric oxide has been
shown to play a significant role as a biological mediator
in the cardiovascular system and in the brain, as well as
in the immune system.1 Superoxide in the form of
form of their oximate anions since the CꢀN bond is
rendered more electron-rich upon deprotonation. Upon
1
combination with O2 the 1-peroxy-1-nitroso intermedi-
ates typically undergo oxidative CꢀN cleavage to give
mixtures of esters, carboxylic acids and aldehydes (from
aldoximate anions) or ketones (from ketoximate
anions), respectively. Our studies showed that ami-
doximes likewise do not participate in photooxygena-
tions unless they are converted to the corresponding
amidoximate anions with base prior to singlet oxygena-
tion and herein we report on our results from these
reactions.
NOS-Fe(II)-O2 (or NOS-Fe(III)-O2 −) has been impli-
’
cated as the active species in these oxidations.2–4 Liver
cytochrome enzymes P450 have also been shown to
catalyze the oxidative cleavage of the CꢀNOH bonds in
ketoximes, amidoximes and N-hydroxyguanidines.5
Also potassium superoxide has been shown to
efficiently cleave CꢀN bonds in amidoximes and N-
hydroxyguanidines to give mixtures of amides and
nitriles.6 Previously we reported a survey of the reac-
tions of singlet oxygen with CꢀN containing com-
pounds, including nitrones, nitronate and oximate
anions, silyl nitronates and hydrazones.7,8 In the
present study we have investigated the role of singlet
oxygen (1O2) in the oxidative cleavages of amidoximate
anions. Our results from the these reactions closely
resemble those obtained from model studies on
iron(III) porphyrin catalyzed oxidation of the N-
hydroxyguanidine group under aerobic conditions.9,10
When amidoximes,11 after treatment with sodium
methoxide, were photooxygenated12 in methanol in the
presence of rose bengal at room temperature, the corre-
sponding amidoximates cleanly underwent oxidative
cleavage to give mixtures of amides and nitriles, with
the former as dominant products (Table 1). The prod-
ucts were separated by chromatography on silica gel,
eluting with diethyl ether. Structural identifications rest
1
on H NMR spectra of the purified products, matching
those taken of authentic samples.
Oximes which, except for benzophenone oxime, are
inert toward O2, react readily with the latter in the
A plausible mechanism for the observed oxidations
involves electrophilic attack of the oximate anion by
1O2, followed by extrusion of NO− giving rise to a
carbonyl oxide (3) (Scheme 1). The latter is an excellent
oxygen atom donor and is converted to the amide by
oxygen atom loss.13 Alternatively, tautomerization of 3
to the peroxycarboximidic acid 514 and base-induced
extrusion of H2O2 would then lead to the nitrile 6.15
1
* Corresponding author. Fax: (415) 338 2384; e-mail: ierden@
sfsu.edu
†
This work was presented at the 13th International Conference on
Organic Synthesis (ICOS-13), July 1–5, 2000, in Warsaw, Poland.
‡ On leave from Yildiz Technical University, Department of Chem-
istry, 80270 Sisli-Istanbul, Turkey.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00887-5

8
N. Ocal, I. Erden / Tetrahedron Letters 42 (2001) 4765–4767
4766
Table 1. Products and yields from the singlet oxygenation of amidoximates
Scheme 1.
Table 1 depicts the results from photooxygenations of a
variety of amidoximate anions. In a few cases small
amounts of the corresponding methyl esters were also
isolated, presumably from the amide in the presence of
methoxide ions.
terms of nitric oxide production, and nicely comple-
ments other model studies using Fe(III) porphyrin
catalysis, directed at elucidating the oxidative processes
involved in the NOS mediated amidoximate cleavages.
Moreover, cleavage reactions of CꢀN containing com-
1
pounds with O2 constitute clean, high-yield and envi-
The conversion of amidoximes to nitriles is remarkable
in that it represents a net loss of NH2OH, a transforma-
tion without precedent in singlet oxygen chemistry. Our
results should provide insight into the mechanistic
details of the nitric oxide synthase reaction since some
of the intermediates postulated in the aforementioned
reaction resemble those proposed in this report.
ronmentally friendly oxidative methods in organic
chemistry. Our studies on the photooxygenations of
other CꢀN containing compounds, including a-oximi-
noketones, are forthcoming.
Acknowledgements
The present study provides a nonenzymatic alternative
to the oxidative cleavage of the amidoxime moiety in
-arginine, a process of considerable importance in
We are grateful for financial support from the National
Science Foundation Grant (Grant CHE-9729001) and a
L

8
N. Ocal, I. Erden / Tetrahedron Letters 42 (2001) 4765–4767
4767
NATO post-doctoral fellowship, administered by
Tubitak of Turkey, to Dr. Ocal. The authors acknowl-
edge partial support of this investigation by a ‘Research
Infrastructure in Minority Institutions’ award from the
National Center for Research Resources with funding
from the Office of Research on Minority Health,
National Institutes of Health No. 5 P20 RR11805.
Tetrahedron Lett. 1993, 34, 793.
8
9. Groves, J. T.; Wang, C. C.-Y. 213th ACS National
Meeting, San Francisco, CA, 1997, paper No. 321.
10. Wang, C. C.-Y.; Ho, D. M.; Groves, J. T. J. Am. Chem.
Soc. 1999, 121, 12094.
11. For typical procedures for the synthesis of amidoximes,
see (a) Eloy, F.; Lenaers, R. Chem. Rev. 1962, 62, 155; (b)
Judkins, B. D.; Allen, D. G.; Cook, T. A.; Evans, B.;
Sardharwala, Synth. Comm. 1996, 26, 4351. Phenyl-
propanamidoxime (entry e): mp. 87°C. Anal. calcd for
C9H12N2O: C, 65.83; H, 7.37; N, 17.06. Found: C, 65.88;
H, 7.44; N, 17.24. 2,2-Dimethylcyclopropylmethanamid-
oxime (entry f): mp 103°C. Anal. calcd for C6H12N2O: C,
56.23; H, 9.44; N, 21.86. Found: C, 56.18; H, 936; N,
21.27.
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