Synthesis of a 13C,15N labeled imidazole and characterization of the 2,5-endoperoxide and its decomposition

Article abstract of DOI:10.1016/S0040-4039(00)01731-7

A synthesis of ¹³C, ¹⁵N labeled imidazoles was developed which allows the direct detection of a transient 2,5-endoperoxide at -100°C. The endoperoxide was thoroughly characterized by ¹H, ¹³C, and ¹⁵N NMR. Upon warming, the endoperoxide decomposes via a series of transient intermediates to ¹³CO₂ and 1,2-diphenyl-ethanediimine. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01731-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9623–9626
13
Synthesis of a C,15N labeled imidazole and
characterization of the 2,5-endoperoxide and its
decomposition†
Ping Kang and Christopher S. Foote*
Department of Chemistry and Biochemistry, University of California, Los Angeles,
CA 90095-1569, USA
Received 7 August 2000; revised 29 September 2000; accepted 3 October 2000
Abstract
A synthesis of 13C, 15N labeled imidazoles was developed which allows the direct detection of a
1
transient 2,5-endoperoxide at −100°C. The endoperoxide was thoroughly characterized by H, 13C, and
15N NMR. Upon warming, the endoperoxide decomposes via a series of transient intermediates to 13CO2
and 1,2-diphenyl-ethanediimine. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: 13C, 15N labeled imidazoles; singlet oxygen; endoperoxide; carbon dioxide.
In a study of the mechanism of photosensitized oxidation of guanosine, we found that the 8-C
of guanosine is oxidized to form CO2 (Scheme 1). Only the 5-membered imidazole ring was
cleaved, leaving the 6-membered ring intact.1 Because of the structural similarity of imidazole
and guanosine, we looked for reports of CO2 formation in the photosensitized oxidation of
imidazoles but found none.2–9
O
N
O
N
1O2
N
O
NH
HN
H2N
HN
HN
R =
TBDMSO
+
H
CO2
OTBDMS
N
R
NH
R
OTBDMS
Scheme 1. CO2 formation in photosensitized oxidation of a guanosine derivative
We were also able to detect several transient intermediates in the photosensitized oxidation of
an 8-13C labeled guanosine derivative by low temperature NMR. For unlabeled 4,5-diphenylim-
* Corresponding author. Tel: (310) 825-1409; fax: (310) 206-1843; e-mail: foote@chem.ucla.edu
†
Dedicated to Professor Harry Wasserman on the occasion of his 80th birthday.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01731-7

9624
idazole, no transient intermediates could be detected other than the endoperoxide. In order to
characterize possible transient species, we have prepared 2-13C-1,3-15N-4,5-diphenylimidazole
and now report characterization of the 2,5-endoperoxide and some of its decomposition
products.
In order to synthesize the 13C, 15N labeled imidazole, we evaluated various synthetic
routes.10–18 Most of the methods are not suitable because of lack of availability of labeled
starting material. We chose a procedure reported by Bakibaev et al.18 and Novelli.17 A mixture
of 15N-urea and 13C-formic acid was heated at 150°C for 4 hours. Benzoin was then introduced
and the reaction mixture heated at 180°C for 3 hours. The product was suspended in water.
After filtration, the powder was resuspended in 5% HCl and heated to 80–90°C. The filtrate was
treated with an excess of NH3 to give pure 4,5-diphenylimidazole in 80% yield (Scheme 2). This
method should also be applicable to the synthesis of other 13C and 15N labeled imidazoles.
Ph
N*
C*
N*
H
O
O
13C
O
OH
Ph
150 °C
4 h
180 °C
3 h
HC*OOH
+
N*H2
+
N*H2
H
N*H2
Ph
Ph
* = label or not, depending on reaction.
Scheme 2. Syntheses of 13C, 15N isotope labeled 4,5-diphenylimidazole
This synthetic method is versatile and selective. We prepared 1,3-15N-4,5-diphenylimidazole,
2-13C-4,5-diphenylimidazole, and 2-13C-1,3-15N-4,5-diphenylimidazole, respectively. In all three
cases, the incorporation of isotope into imidazole is almost 100%. The structures of labeled
1
imidazoles were confirmed by H NMR, 13C NMR, and high resolution MS. We also observed
1
1
splitting of the H peak by 13C and 15N, and of the 13C peak by H and 15N (Table 1). Splitting
of the 15N peak by H and 13C was not observed in the imidazole, but was detected in the
1
products. These magnetic interactions are very useful in the identification of the transient
intermediates.
Table 1
1H/13C/15N couplings (Hz) in 2-13C-1,3-15N-diphenylimidazole and 2,5-endoperoxide
J1Hꢀ1N
J1Nꢀ1H
J2Cꢀ2H
J2Hꢀ2C
J2CꢀN
JNꢀ2C
J2HꢀN
13C,15N imidazole
2,5-Endoperoxide
96.4
69.7
n/a
70.0
207.1
193.5
207.0
194.5
5.0
4.9, 5.1
n/a
n/a
10.3
4.9, 5.3
The synthesis of labeled imidazole also provides some information on the mechanism of the
hydroamination of ketone by urea in formic acid. It was reported that the thermal dissociation
of methylurea involves two paths: the formation of methylamine and isocyanic acid, and the
formation of ammonia and methylisocyanate.12 Bakibaev et al.18 suggested that the formamide
is formed from the isocyanic acid and not from formic acid. Our observation that the 13C of the
formic acid is totally incorporated into imidazole indicates that 13C formamide is formed from
ammonia and formic acid, and reacts with benzoin to give 4,5-diphenylimidazole. The second
nitrogen presumably comes either from formamide or ammonia, which is present in the reaction
mixture (odor).

9625
Photosensitized oxidation of 13C and/or 15N labeled 4,5-diphenylimidazole was carried out in
a 5 mm NMR tube at −100°C under oxygen with ca. 5×10−5 M 2,9,16,23-tetra-tert-butyl-
29H,31H-phthalocyanine as sensitizer and a Cermax 300w Xenon lamp as the light source. A
chromium glass filter was used to cut off wavelengths below 547 nm. The starting material was
dissolved in a solvent mixture of acetone-d6 and fluorotrichloromethane (1:5, ca. 0.04 M). After
1 hour of photolysis, the tube was transferred to a precooled NMR probe. We detected one
intermediate by NMR at −100°C. This was assigned as the 2,5-endoperoxide based on the NMR
1
spectra. In the H NMR, the 2CꢀH of the starting material (at 7.75 ppm) disappeared, and a
new peak appeared at 6.92 ppm, split by the 2-13C and by the 1,3-15N. (Table 1) The NH peak
(12.3 ppm at −80°C for starting material) was at 5.06 ppm in the endoperoxide, split by 1-15N.
13C NMR shows the 2-13C peak shifted from 135.6 to 102.1 ppm. This is a tertiary carbon split
by the 2-H, and also by 1,3-15N, which indicates that the 5-membered ring is intact. An HMQC
spectrum confirmed the coupling between the 102.1 ppm carbon and the 6.92 ppm hydrogen.
There are two peaks in the 15N NMR spectrum, at 307.0 and 111.6 ppm. The first peak is
assigned to the 3-15N and the second to the 1-15N because the 111.6 ppm peak was split by a
directly bonded hydrogen.
Upon warming the reaction mixture to −88°C, the endoperoxide started to decompose to
several other transient intermediates. We are currently working on the structure assignment of
these intermediates. The final products are 13CO2 (124.5 ppm) and 1,2-diphenyl ethanediimine
(FAB-MS: 209.1 [M+1]+. We isolated the hydrolysis product benzil from the reaction mixture
after workup) (Scheme 3). No starting material was recovered. The decomposition of the
endoperoxide is triggered by the rearrangement of the 1NꢀH, since this peak disappeared as the
endoperoxide decomposed. This observation suggested that substitution of the NꢀH with
N-methyl would stabilize the endoperoxide.
Ph
Ph
N15
Ph
Ph
N15
1O2
15
via several imtermediates
warming to RT
13
H N
N15H
Ph
H
13
13CO2
+
N15
-100 °C
N15
H
O
Ph
O
O
H
Ph
Ph
N15
N15
Ph
N15
Ph
Ph
N15
warming to -28 °C
1O2
H
1O2
13
13
+
N15
Me
-100 °C
N15
Me
O
Ph
Me
Scheme 3. 2,5-Endoperoxide formation
The photosensitized oxidation of N-methyl-4,5-diphenylimidazole was carried out under
similar conditions. The endoperoxide (2C at 105.1 ppm) is much more stable than the
unmethylated derivative, and does not decompose until −28°C. The decomposition of the
endoperoxide regenerated the starting material as the main product (Scheme 3). Adding a
methyl to the 1N position of the imidazole totally changes the reaction pathway of the
endoperoxide rearrangement, which suggests that proton transfer from the NꢀH is much more
facile than the extrusion of oxygen.7

9626
In summary, an efficient synthesis of 13C monolabeled, 15N double labeled, and 13C, 15N triple
labeled 4,5-diphenylimidazole from readily available 13C formic acid and 15N urea was devised.
The 2,5-endoperoxide from the photosensitized oxidation of the labeled imidazole was charac-
terized. Upon warming, the endoperoxide decomposed via a series of transient intermediates to
13CO2 and 1,2-diphenyl-ethanediimine.
Acknowledgements
This work was funded by NSF grant CHE97-03086.
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