R. A. Martinez et al.
and the appearance of a resonance at 169.9 ppm (13C=O of 6). The reac- vacuum/pressure gauge, and the reaction flask could be affixed and iso-
tion mixture was filtered through a celite-packed frit funnel to remove lated by metering valves. The 250-mL lecture bottle was evacuated and
the AmberlystW. The volatiles were removed using a rotary evaporator tared. [13C]Carbon dioxide (3.6 g, 0.08 mol, 1.0 equiv) was condensed into
to yield 6 as a slightly yellow and viscous liquid (142 g, 96.6%), which the lecture bottle, and the quantity of 13CO2 was verified by the change
was used without further purification. Using the same procedure, 2 was in mass of the lecture bottle. The rest of the reagents were scaled to the
prepared from 2-(phenylthio)[1,2-13C2]acetic acid (1) in 98.1% yield. Com- amount of 13CO2. Then, methyl phenyl sulfide (19.9 g, 0.16 mol, 2.0 equiv)
3
pound 6 1H NMR (CDCl3, 300 MHz): d = 1.22 (t, JHH = 7.2Hz, 3H, CH3), was added to a 1-L round-bottom flask equipped with a magnetic stir bar
3.63 (d, 2JCH = 5.5 Hz, 2H, SCH2), 4.16 (dq, 3JCH = 3.2 Hz, 3JHH = 7.2 Hz, 2H, and placed under a stream of argon. Anhydrous THF (300 mL) was added
OCH2), 7.20–7.43 (m, 5Harom). 13C NMR (CDCl3, 75 MHz): d = 14.3 (d, 3JCC = 2.0 to the flask, and this solution was cooled to À78 ꢀC. To this solution, sec-
1
2
Hz, CH3), 36.9, (d, JCC = 61.9 Hz, SCH2), 61.7 (d, JCC = 2.5Hz, CH2), 127.1 butyllithium (1.4 M, 129 mL, 0.180 mol, 2.2 equiv) was added dropwise
(Carom), 129.2 (Carom), 130.2 (Carom), 135.2, 169.9 (13C=O). Compound 2 H over 10 min and monitored to ensure complete formation of the anion
1
NMR (CDCl3, 300 MHz): d = 1.22 (t, 3JHH = 7.2 Hz, 3H, CH3), 3.63 (dd, 2JCH = 5.4 as described earlier. The reaction flask containing the (phenylthio)methyl
Hz, JCH = 141.3 Hz, 2H, S13CH2), 4.16 (dq, JCH = 3.2 Hz, JHH = 7.2Hz, 2H, lithium was evacuated three times until the solvent boiled vigorously
1
3
3
OCH2), 7.20–7.43 (m, 5Harom). 13C NMR (CDCl3, 75 MHz): d = 14.3 (d, 3JCC = 2.0 (0.1–0.2 mBar ꢁ vapor pressure of THF atÀ78 ꢀC). Then, 13CO2 was slowly
1
2
Hz, CH3), 36.9, (d, JCC = 61.9Hz, S13CH2), 61.7 (d, JCC = 2.5Hz, CH2), 127.1 introduced into the reaction vessel through a metering valve over
(Carom), 129.2 (Carom), 130.2 (Carom), 135.2 (Carom), 169.9 (d, JCC = 61.9 Hz, approximately 30 min. During the addition of 13CO2, the pressure in the
1
13C=O).
reaction flask was always below atmospheric pressure. The addition of
13CO2 was judged complete when the pressure in the system returned
to ~0.1–0.2 mBar after which the reaction was stirred for 1 h. The mixture
was then brought to room temperature while stirring for an additional
2 h. The reaction was quenched by adding distilled water (100 mL). The
reaction mixture was extracted with hexane (3Â, 100 mL) to remove
methyl phenyl sulfide. The aqueous layer was then acidified using hydro-
chloric acid (6 N) to pH = 2. At this time, compound 5 precipitated as a
white solid. The heterogeneous aqueous layer was then extracted with
ethyl acetate (3Â, 200 mL). The ethyl acetate layer was then dried over
solid sodium sulfate and filtered, and volatiles were removed using a rotary
evaporator to yield a yellowish solid (13.1g, 97% based on 13CO2) that can
be used without further purification. 1H NMR (CDCl3, 300MHz): d = 3.67 (d,
2JCH = 5.3 Hz, 2H, SCH2), 7.18–7.50 (m, 5Harom), 10.96 (bs, 1H, OH). 13C NMR
Ethyl 2-(phenysulfinyl)[1,2-13C2]acetate (3)
Ethyl 2-(phenylthio)[1,2-13C2]acetate (2) (10.0 g, 0.05 mol, 1.0 equiv) was
dissolved in a 50% solution of methanol in distilled water (100 mL). Then,
sodium periodate (13.0 g, 0.06 mol, 1.2 equiv) was added. The resulting
solution was stirred at room temperature using a magnetic stir bar.
Product formation was monitored by 13C NMR noting the disappearance
of resonance doublets at 36.9 (S13CH2 of 2) and 169.9 ppm (13C=O of 2)
and the appearance of resonance doublets at 61.7 (S13CH2 of 3) and
164.5 ppm (13C=O of 3). A white precipitate formed after approximately
30 min. The mixture becomes very thick, and more solvent (100 mL)
was added to allow continuous stirring. After approximately 24 h, the
reaction was determined to be complete by 13C NMR. The white precipi-
tate was then filtered, and most of the methanol was removed using a
rotary evaporator. The aqueous phase was extracted with ethyl acetate
(3Â, 200 mL). The organic layer was dried over sodium sulfate and
filtered, and the volatiles were removed by a rotary evaporator to obtain
a clear, colorless oil (10.7 g, 99%) that was used without further purifica-
1
(CDCl3, 75 MHz): d = 36.8, (d, JCC = 59.5Hz, SCH2), 127.5 (Carom), 129.4
(Carom), 130.3 (Carom), 134.6 (d, 3JCC = 1.1Hz, Carom), 176.1 (13C=O). Elemental
analysis of 5: Calculated: 13CC7H8O2S: C, 57.37; H, 4.77; S, 18.95. Found: C,
57.44; H, 4.73; S, 18.88. Melting point of 63.9ꢀC, literature value 63.5ꢀC40
.
2-(Phenylthio)[2-13C]acetic acid (7)
tion. 1H NMR (CDCl3, 300 MHz): d = 1.19 (t, JHH = 7.1 Hz, 3H, CH3), 3.81
3
1
AB
(dddd, JCH = 141.8 Hz,
J
= 39.3 Hz; 13.8 Hz; 6.1 Hz, 2H, S13CH2), 4.13
HH
The [13C]methyl phenyl sulfide15 (20.1 g, 0.160 mol, 2.0 equiv) was added
to a 1-L round-bottom flask equipped with a magnetic stir bar and
placed under a stream of argon. Anhydrous THF (200 mL) was added to
the flask, and this solution was cooled to À78 ꢀC. To this solution, sec-
butyllithium (1.4 M, 129 mL, 0.180 mol, 2.2 equiv) was added dropwise
over a 10-min period and monitored to ensure complete formation of
the anion as described earlier. An excess of CO2 was bubbled through
the reaction until a white precipitate formed. The mixture was then
allowed to come to room temperature while stirring for an additional
2 h. The reaction was quenched by adding distilled water (100 mL). The
reaction mixture was extracted with hexane (3Â, 100 mL) to remove
unreacted [13C]methyl phenyl sulfide, which was recovered by evapora-
tion of the solvent using a rotary evaporator. The aqueous layer was
acidified using hydrochloric acid (6 N) to pH = 2, which caused 7 to
precipitate as a colorless solid. The heterogeneous aqueous layer was
then extracted with ethyl acetate (3Â, 200 mL). The combined ethyl
acetate fractions were dried over solid sodium sulfate, filtered, and
evaporated to yield a colorless solid (13.53 g, 99.6%) that was used without
further purification. The recovered [13C]methyl phenyl sulfide (8.4g, 84%)
was used in subsequent reactions without further purification. 1H NMR
3
3
(dq, JHH = 7.1 Hz, JCH = 3.2 Hz, 2H, OCH2), 7.21–7.83 (m, 5Harom). 13C
NMR (CDCl3, 75 MHz): d = 13.7 (d, 3JCC = 2.0 Hz, CH3), 61.1 (d, 1JCC = 60.2 Hz,
S
13CH2), 61.7 (d, 2JCC = 2.0 Hz, CH2), 123.9, 129.1, 131.5, 142.4 (d, 2JCC = 2.2
Hz, Carom), 164.5 (d, 1JCC = 60.2 Hz, 13C=O).
Ethyl 2-(phenylsulfonyl)[1,2-13C2]acetate (4)
Oxone (44.6g, 0.072 mol, 3.0equiv) was dissolved in distilled water (200mL)
and the solution stirred with a magnetic stir bar. Ethyl 2-(phenylthio)
[1,2-13C2]acetate (2) (4.8g, 0.024mol, 1.0equiv) was dissolved in a 50% solu-
tion of ethanol in ethyl acetate (50 mL) and added dropwise to the stirred
oxone solution. The resulting solution was incubated at room temperature
for 3 h with continued stirring. Product formation was monitored by 13C NMR
noting the disappearance of resonance doublets at 36.9 (S13CH2 of 2)
and 169.9 ppm (13C=O of 2) and the appearance of resonance doublets at
61.1 (S13CH2 of 4) and 162.4 ppm (13C=O of 4). After oxidation was
complete, the solution was extracted (3Â, 200 mL) with ethyl acetate. The
organic layer was dried over sodium sulfate and then filtered. The volatiles
were removed using a rotary evaporator to obtain a clear, colorless oil
(4.94 g, 88.6%) that was used without further purification. 1H NMR
1
(CDCl3, 300MHz): d = 3.66 (d, JCH = 141.3 Hz, 2H, S13CH2), 7.17–7.49
3
2
(CDCl3, 300 MHz): d = 1.18 (t, JHH = 7.1 Hz, 3H, CH3), 4.14 (dd, JCH = 6.6
(m, 5Harom), 10.68 (bs, 1H, OH). 13C NMR (CDCl3, 75 MHz): d = 36.8,
Hz, JCH = 140.1 Hz, 2H, S13CH2), 4.14 (dq, JCH = 3.3 Hz, JHH = 7.1 Hz,
2H, OCH2), 7.52–7.98 (m, 5Harom). 13C NMR (CDCl3, 75 MHz): d = 13.9
(d, 3JCC = 2.2 Hz, CH3), 61.1, (d, 1JCC = 60.7 Hz, S13CH2), 61.7 (dd, 3JCC = 1.0
Hz, 2JCC = 2.7 Hz, OCH2), 128.6 (Carom), 129.3 (Carom), 134.4 (Carom), 138.8
(d, 3JCC = 8.3 Hz, Carom), 162.4 (d, 1JCC = 60.7 Hz, 13C=O).
1
3
3
3
1
(s, S13CH2), 127.5, 129.4, 130.2 JCC = 1.9 Hz, 134.6, 176.5 (d, JCC = 59.5
Hz, C=O); Melting point of 64 ꢀC, literature value 63.5 ꢀC40
.
Acknowledgements
2-(Phenylthio)[1-13C]acetic acid (5)
This work was funded in part by the National Stable Isotope
This reaction was carried out using a pressure/vacuum manifold to which Resource at the Los Alamos National Laboratory (NIH grant award
the 13CO2 supply cylinder, a 250-mL stainless steel lecture bottle, a P41RR02231) and by the New Mexico Highlands University.
Copyright © 2013 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2013, 56 31–35