Synthesis of N-[1-13C]caproyl-N′-phenylthiourea

Article abstract of DOI:10.1002/jlcr.859

An optimal synthesis of N-[1-¹³C]caproyl-N′-phenylthiourea with isotopic enrichment 82% is described, starting from barium [ ¹³C]carbonate, using five synthetic steps. Yields were 95% relative to caproyl chloride and 46% relative to barium carbonate. Oxidation of the title compound with manganese dioxide yields the corresponding ureide. Structural similarities with anticonvulsants such as phenacemide make N-caproyl-N′- phenylthiourea an interesting model compound. Copyright

Full text of DOI:10.1002/jlcr.859

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2004; 47: 719–722.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.859
Research Article
Synthesis of N-[1-13C]caproyl-N0-phenylthiourea
Corina Anca Simion1, Cristian Postolache1, Calin Deleanu2, Ileana Chirtoc3,
Catalina Mihaela Barna1, Ioana Bally1 and Alexandru T. Balaban4,*
1 National Institute for Research & Development of Physics and Nuclear Engineering,
407 Atomistilor Street, P.O. Box MG 6 – Magurele, 077125 Bucharest, Romania
2 Institute of Organic Chemistry ‘‘C. D. Nenitzescu’’ of the Romanian Academy, 212B
Splaiul Independentei, Bucharest, Romania
3 National Institute for Research & Development of Isotopic and Molecular
Technologies, 71-103 Donath Street, P.O. Box 700, 400293 Cluj-Napoca, Romania
4 Texas A&M University at Galveston, 5007 Avenue U, Galveston, TX 77551, U.S.A.
Summary
An optimal synthesis of N-[1-13C]caproyl-N0-phenylthiourea with isotopic enrichment
82% is described, starting from barium [13C]carbonate, using five synthetic steps.
Yields were 95% relative to caproyl chloride and 46% relative to barium carbonate.
Oxidation of the title compound with manganese dioxide yields the corresponding
ureide. Structural similarities with anticonvulsants such as phenacemide make
N-caproyl-N0-phenylthiourea an interesting model compound. Copyright # 2004
John Wiley & Sons, Ltd.
Key Words: barium [13C]carbonate; 1-[13C]caproic acid; 1-[13C]caproyl isothiocya-
nate; N-[1-13C]caproyl-N0-phenylthiourea; phenacemide
Introduction
Many ureides and thioureides exhibit interesting biological activity. Among
them, N-caproyl-N0-phenylthiourea is closely similar to classical anticonvul-
sants such as phenacemide and ethylphenacemide.1,2 Carbon-labelled analo-
gues of N-caproyl-N0-phenylthiourea and N-caproyl-N0-phenylurea may be
useful for pharmacokinetic and pharmacodynamic studies, as well as for
metabolic investigations. These types of investigations have been described in
detail.3
A five-step synthesis of N-[1-13C]caproyl-N0-phenylthiourea (7) is described,
starting from barium [13C]carbonate with 82% isotopic enrichment. Manga-
*Correspondence to: A. T. Balaban, Texas A&M University at Galveston, 5007 Avenue U, Galveston,
TX 77551, U.S.A. E-mail: balabana@tamug.edu
Copyright # 2004 John Wiley & Sons, Ltd.
Received 8 December 2003
Revised 15 April 2004
Accepted 7 June 2004

720
C. A. SIMION ET AL.
nese dioxide may be employed to convert 7 into N-[1-13C]caproyl-N0-
phenylurea at room temperature in chloroform solution.4
Results and discussion
Commercial barium [13C]carbonate with 82% isotopic enrichment (1) was
employed for carbonating (2) the Grignard reagent.5 The resulting salt (3) was
converted into 1-[13C]caproic acid (4), which was extracted into ethyl ether.
1
Both 13C- and H-NMR spectra were used to characterize compound 4. The
acid chloride (5) was then prepared with thionyl chloride, and 5 was treated
with an excess of ammonium thiocyanate, whereupon caproyl isothiocyanate
(6) was formed (an analogous reaction for a-phenylthiourea has been
described6). The five synthetic steps are presented in Figure 1.
Since the formation of 6 is a critical step in the synthesis, the reaction
conditions were optimized. We found that 25 min refluxing in anhydrous
acetone was optimal for consuming all the caproyl chloride. A previous
report4 gave 5 min as sufficient for this reaction, but the presence of unreacted
acid chloride leads to the formation of an anilide as a by-product, and this by-
product is difficult to separate from the target compound. In order to avoid
any thermal decomposition, the next step (dropwise addition of aniline to 6
under mechanical stirring) was carried out at 258C. The formation of the
target compound, N-[1-13C]caproyl-N0-phenylthiourea (7), was monitored by
TLC. The product was precipitated by addition of methanol, and purified by
CH3(CH2)4MgBr
HClO4 35%
CH3(CH2)413COOMgBr
13CO2
Ba13CO3
(3)
(2)
(1)
H+
CH3(CH2)413COOH
CH3(CH2)413COOMgBr
+ HOH
(4)
(3)
SOCl2
CH3(CH2)413COCl
(5)
CH3(CH2)413COOH
(4)
NH4SCN
CH3(CH2)413CONCS
CH3(CH2)413COCl
(6)
(5)
PhNH2
CH3(CH2)413
CH3(CH2)413CONCS
CONHCSNHPh
(7)
(6)
Figure 1. The five reaction steps 1 –> 3 –> 4 –> 5 –> 6 –> 7 for the synthesis
of 7 from Ba13CO3
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 719–722

SYNTHESIS OF N-[1-13C] CAPROYL-N0-PHENYLTHIOUREA
721
recrystallization from aqueous methanol. The overall yield was 46% with
respect to Ba13CO3, and the yield relative to the acid chloride was 95%.
The 13C labeling at the carbonyl group was confirmed by both NMR
analysis and EI-MS study. The 13C-NMR spectrum contains the enriched
peak at 174.22 ppm. The mass spectrum contains the molecular peaks M at m/
z=250 and 251, indicating an 82% enrichment. As expected, the fragmenta-
tion pattern preserves the same enrichment ratio for the ions with m/z=193
and 194 (M – C3H7), and 207 and 208 (M – C4H9).
Experimental
Chemicals were obtained from commercial sources: Monsanto Research
Corporation for Ba13CO3, and Merck for other chemicals. The NMR spectra
were recorded at 208C in CDCl3, using a Bruker Avance 400 DRX at 400 MHz
1
for H spectra and 100 MHz for 13C analyses. Chemical shifts (d, ppm) are
reported relative to internal tetramethylsilane. The electron-impact mass
spectra were recorded with a double-focusing MAT mass spectrometer at an
ionization energy of 70 eV. The samples were introduced directly into the ion
source and heated gradually in vacuum from 20 to 2508C.
N-[1-13C]caproyl-N0-phenylthiourea (7)
[1-13C]caproic acid (4) was prepared from 1.1 mmol of n-pentylmagnesium
bromide (obtained by adding 1-bromopentane to magnesium turnings in
diethyl ether and refluxed until completion of the reaction) and [13C]carbon
dioxide was generated from 200 mg (1 mmol) of barium [13C]carbonate and
35% perchloric acid (4.0 ml, 5 mmol). The resulting salt (3) was quenched with
dilute sulfuric acid, the acid 4 was extracted into 20% aqueous sodium
hydroxide (10 ml). After extraction with diethyl ether the aqueous layer was
acidified, the acid was extracted in diethyl ether, and the solvent was
evaporated under vacuum. Refluxing of 4 with excess thionyl chloride and
fractionation under vacuum afforded [1-13C]caproyl chloride (5) in 50% yield
relative to Ba13CO3.
Ammonium thiocyanate (114 mg, 1.5 mmol) in anhydrous acetone (10 ml)
was stirred magnetically until dissolution was complete. A solution of
[1-13C]caproyl chloride (68 mg, 0.5 mmol) in anhydrous acetone (10 ml) was
then added from a dropping funnel, and the solution was refluxed for 25 min.
After cooling to 08C, a solution of aniline (140 mg, 1.5 mmol) in anhydrous
acetone (10 ml) was added, and the mixture was left at 0–58C overnight. Cold
methanol (5 ml) was added to complete the precipitation of the reaction
product (7), which was isolated by filtration, washed on the filter with cold
methanol, and recrystallized from aqueous methanol 1:3 (v/v). Compound 7
(112 mg, 95% yield relative to 5) was obtained as fluffy white crystals with m.p.
77–788C, in agreement with the reported data.7,8
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C. A. SIMION ET AL.
1H-NMR (d, ppm): 0.92 (t, JHH = 7.2 Hz, 3H), 1.35 (m, 2H), 1.36 (m, 2H),
1.71 (m, 2H), 2.39 (dd, JHH=7.3 Hz, JCH=10.4 Hz, 2H), 7.28 (d, JHH=8 Hz,
2H), 7.40 (t, JHH=8 Hz, 1H), 7.64 (d, JHH=8 Hz, 2H), 8.75 (s, 1H), 12.48 (s,
1H) (400 MHz, CDCl3).
1
13C-NMR (d, ppm): 13.85, 22.31, 24.43, 31.15, 37.39 (d, JCC=50.0 Hz, a-
CH2), 124.18, 126.91, 128.89, 137.51, 174.22 (C=O), 178.05 (C=S) (100 MHz,
CDCl3).
Conclusions
Optimal reaction conditions for preparing N-[1-13C]caproyl-N0-phenylthiourea
(7) in 5 steps were determined, starting from barium [13C]carbonate and n-
pentylmagnesium bromide, followed by reaction with ammonium thiocyanate,
and then with aniline.
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Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 719–722