Synthesis of isotopically labelled 2-isopropylthioxanthone from 2,2′-dithiosalicylic acid and deuterium cumene

Article abstract of DOI:10.1002/jlcr.3400

Two efficient synthetic routes of stable deuterium labelled 2-isopropylthioxanthone were presented with 98.1% and 98.8% isotopic abundance in acceptable yields and excellent chemical purities. Their structures and the isotope-abundance were confirmed according to proton nuclear magnetic resonance and liquid chromatography–mass spectrometry.

Full text of DOI:10.1002/jlcr.3400

Research article
Received 01 February 2016,
Revised 09 March 2016,
Accepted 21 March 2016
Published online 28 April 2016 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3400
Synthesis of isotopically labelled 2-
isopropylthioxanthone from 2,2′-
dithiosalicylic acid and deuterium cumene
Chao Fang, Weicheng Yang, Chao Yang, Haoran Wang, Kai Sun and
*
Yong Luo
Two efficient synthetic routes of stable deuterium labelled 2-isopropylthioxanthone were presented with 98.1% and 98.8%
isotopic abundance in acceptable yields and excellent chemical purities. Their structures and the isotope-abundance were
confirmed according to proton nuclear magnetic resonance and liquid chromatography–mass spectrometry.
Keywords: 2-isopropylthioxanthone; labelled internal standards; two synthetic routes; deuterium cumene
cumene.9 In this paper, we would like to report an efficient
preparation for two kinds of labelled ITX using deuterium
Introduction
cumene as precursor specifically.
2-isopropylthioxanthone (ITX) is recognized as a typical example
of commercially available photoinitiators which are useful as
photoinitiators and activators for the photopolymerization of
unsaturated compounds that cure or crosslink upon exposure
to ultraviolet radiation.1,2 It is widely used in the production of
photocurable surface coatings and inks.3,4 However, recent
studies have found that the residue of 2-isopropylthioxanthone
in inks after heating or irradiation could penetrate into food
packaging materials and contaminate food, which might pose
a potential risk for human health.5 Therefore, it has become a
vital detection index in the international food trade, such as
the European Union, USA, China and Japan.6,7
In recent years, numerous methods have been developed for
the determination of 2-isopropylthioxanthone, including high-
performance liquid chromatography, gas chromatography–mass
spectrometry (GC-MS) and liquid chromatography–mass
spectrometry (LC-MS).5–7 But, these methods had some defects
for determining the residue of 2-isopropylthioxanthone in the
contaminated food because of the interference from other
impurities and losses in the sample purification process.8 More
prominent and reliable analytical methods had aroused the
interest of researchers. Liquid chromatography isotope diluted
tandem mass spectrometry was proved sensitive and reliable
among various analytical approaches, which could adjust for
the losses in sample pretreatment and purification, offset the
error caused by ion suppression in the mass spectrometric
detection process, and made the results closer to the true value
efficiently.
Results and discussion
Although the manufacture of 2-isopropylthioxanthone is fairly
common on industrial scale, reports of the preparation of
isotopically labelled 2-isopropylthioxanthone or its analogues
have not been found in the literature. 2012, Park synthesized
2-isopropylthioxanthone from DTSA and isopropylbenzene.9 His
work brought us inspiration that two efficient synthetic routes
for deuterium labelled 2-isopropylthioxanthone could be
developed with two kinds of labelled intermediates by labelling
deuterium on benzene ring and isopropyl separately. The four-
step synthesis of the labelled product 5 and the five-step
synthesis of the labelled product 12, respectively, started with
labelled raw materials D6-benzene 1 and D6-acetone 6. Our
approach to the synthesis is summarized in Scheme 1.
In route one, D5-bromobenzene 2 (99.6% atomD, 52.6% yield)
was obtained via substitution reaction of D6-benzene 1 with the
equal amount of N-Bromosuccinimide (NBS) in the presence of
FeCl3 as the catalyst and at 100 °C. Through preparation of
Grignard solution 3 with D5-bromobenzene 2 and magnesium
filings, D5-cumene 4 was obtained with 99.6% atomD from 2-
bromopropane and D5-Grignard reagent 3 in the presence of
Research and Development Center, Shanghai Research Institute of Chemical
Industry, 345 East Yunling Road, Shanghai, 200062, China
To the best of our knowledge, there were very few procedures
described in the literature for the synthesis of labelled 2-
isopropylthioxanthone. Park reported the synthesis of unlabelled
*Correspondence to: Yong Luo, Research and Development Center, Shanghai
Research Institute of Chemical Industry, 345 East Yunling Road, Shanghai
200062, China.
2-isopropylthioxanthone from dithiosalicyclic acid (DTSA) and E-mail: real-luoyong@hotmail.com
J. Label Compd. Radiopharm 2016, 59 313–316
Copyright © 2016 John Wiley & Sons, Ltd.

C. Fang et al.
Scheme 1. Synthesis of isotopically labelled 2-isopropylthioxanthone.
Co(acae)3 and tetramethylethylenediamine (TMEDA) as the
Reagents and conditions: (i) NBS, FeCl3, CH3CN, 100 °C, 7 h,
catalyst at 15 °C (81.8% yield over 2 steps). The synthesis of 52.6%a, 99.6% atomDb; (ii) Mg filings, THF, ref, 1 h; (iii) 2-
labelled cumene is important for corresponding labelled bromopropane, Co(acae)3, TMEDA, 15 °C, 12 h, 81.8%, 99.6%
analogues. D5-cumene 4 was further coupled with DTSA at room atomD; (iv) DTSA, D2SO4, D2O, rt, 4 h, 35%, 98.1% atomD; (v)
temperature in the presence of D2SO4 to generate D3-2- LiAlH4, diglyme, diethylene glycol, 0 °C, 1 h, 92.3%, 99.6% atomD;
Isopropylthioxanthone 5 with 98.1% atomD according to its (vi) P(Br)3, rt, overnight, 72.5%, 99.6% atomD; (vii) Mg filings, THF,
Mass Spectra (MS) spectrum of Figure 1 (35.0% yield).
ref, 1 h; (viii) Co(acae)3, TMEDA, 15 °C, 12 h, 82.0%, 99.6% atomD;
In the route two, D6-acetone 6 was reduced with the moiety and (ix) DTSA, D2SO4, D2O, rt, 4 h, 32.0%, 98.8% atomD.
amount of LiAlH4 to D6-isopropanol 7 with 99.6% atomD at 0 °
C (92.3% yield). The D6-isopropanol 7 was then converted to
D6-2-bromopropane 8 with 99.6% atomD at room temperature
Experimental
in the presence of phosphorus tribromide (72.5% yield). Through
preparation of Grignard solution 10 with bromobenzene 9 and
General
All reactions were carried out under an atmosphere of nitrogen. All
magnesium filings, D6-cumene 11 was obtained with 99.6%
solvents were purified according to the corresponding methods to
atomD from D6-2-bromopropane 8 and Grignard reagent 10 in
remove water and stored under an atmosphere of dry nitrogen. The
the presence of Co(acae)3 and TMEDA as the catalyst at 15 °C
labelled raw materials were purchased from Sigma-Aldrich. Column
(82.0% yield over 2 steps). D6-2-Isopropylthioxanthone 12
chromatography, and preparative thin-layer chromatography were
(98.8% atomD according to its MS spectrum of Figure 2, 32.0%
carried out by using Merck silica gel 60 (230–400 mesh), respectively.
Proton nuclear magnetic resonance (1H NMR) spectra were recorded
yield) was synthesized with the similar procedure of D6-cumene
11 coupled with DTSA at room temperature in the presence of
D2SO4.
on
a Bruker AC-500 (500 MHz) spectrometer using CDCl3 unless
otherwise stated with Me4Si as an internal standard. MS were obtained
258.02
100
90
80
70
60
50
40
259.03
30
20
216.01
217.02
218.12
260.03
261.02
10
0
257.01
256.18
200205210215220225230235240245250255260265270
m/z
Figure 1. MS spectrum of 5.
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Copyright © 2016 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2016, 59 313–316

C. Fang et al.
261.06
100
90
80
70
60
50
40
30
20
10
0
262.09
263.02
260.02
258.98
228.92
264.08
226.35
220 225 230 235 240 245 250 255 260 265 270
m/z
Figure 2. MS spectrum of 12.
from TSQ Quantum Access spectrometer (Thermo Fisher Scientific,
88 mmol) in anhydrous THF (40 mL) over 30 min under N2 atm. The
Waltham, Massachusetts, USA) equipped with electrospray ionization reaction mixture was stirred under nitrogen at 70 °C for 1 h and then
source and reported as m/z. GC-MS were obtained with Agilent 7890- cooled to room temperature to afford crude 3 which was used in the
7000C spectrometer (Agilent Technologies Inc, Palo Alto, California,
USA) used Agilent HP-5MS 30 m × 0.25 mm, 0.25 μm column. Purity
was determined by high-performance liquid chromatography (Essentia
LC-15C) that used WondaSil C18-WR 4.6 × 150 mm, 5 μm column and
the solvent which contained water and acetonitrile (Figure 3).
next step without further purification.
(D5)-Isopropylbenzene (4)
A dry and nitrogen-flushed 250 mL two-necked flask, equipped with a
nitrogen inlet and a dropping funnel, was charged with 2-bromopropane
(6.1 g, 50 mmol), Co(acae)3 (0.9 g, 2.5 mmol, 5 mol%), TMEDA (0.29 g,
2.5 mmol, 5 mol%) and anhydrous THF (30 mL). The reaction mixture
was cooled to 0 °C, then D5-Grignard solution 3 prepared earlier (60 mL,
55 mmol) was added in 2 h. After completion of the addition, the mixture
was stirred to 15 °C for 12 h and then quenched with water (100 mL). The
excess solid powder was removed by filtration, and the filter cake was
washed with ether (3 × 50 mL), then the combined organic layers were
dried over anhydrous magnesium sulfate and concentrated in vacuum.
The crude product was then distillated under reduced pressure
(10 mmHg,50–60 °C) to give 4 (5.6 g, 45 mmol, 81.8% yield, 99.6% atomD)
as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ ppm: 1.24 (d, J = 9 Hz,
6H), 2.88 (sep, J = 9 Hz, 1H). GC-MS: m/z 110, 125.
(D5)- Bromobenzene (2)
D6-benzene 1 (99.96%atomD, 32.0 g, 410 mmol) was added gradually to
a mixture of N-Bromosuccinimide (73.0 g, 410 mmol) and anhydrous
ferricchloridean (6.6 g, 41 mmol) in acetonitrile (80 mL) at 0 °C. The
reaction mixture was heated to 100 °C and remained for 7 h, followed
by the addition of water (100 mL) to quench the reaction. The excess
Ferric chloride was removed by filtration, and the filter cake was washed
with ether (3 × 80 mL). The combined filtrate was extracted with ether,
washed with brine, dried over anhydrous magnesium sulfate and
concentrated in vacuum. The crude product was then distillated under
reduced pressure (700 mmHg,80–100 °C) to give 2 (34.9 g, 215 mmol,
52.6% yield, 99.6% atomD) as a colorless oil. GC-MS: m/z 54, 82, 161, 162.
(D3)-2-Isopropylthioxanthone (5)
A dry and nitrogen-flushed 100 mL three-necked flask, equipped with a
nitrogen inlet, a thermometer and a reflux condenser with calcium
chloride drying tube, was charged with dithiosalicyclic acid (8.0 g,
26 mmol) and D5-cumene 4 (3.2 g, 26 mmol). Then 20 g of 98% D2-
sulfuric acid was added to this stirred suspension. The reaction mixture
was further stirred at room temperature for 4 h, and 20 g of deuterium
oxide and 100 g of toluene was added portionwise. This organic layer
was seperated, and the acid layer was further extracted with 100 g of
toluene. The combined organic layers were neutralized with a saturated
sodium carbonate solution, washed with water, dried over anhydrous
magnesium sulfate and concentrated in vacuum. The crude product
was then purified by column chromatography on a silica gel column
using petroleum hexane/ethyl acetate (20:1) as eluent to give 5 (2.3 g,
9 mmol, 35% yield, 98.1% atomD).1H NMR (500 MHz, CDCl3) δ ppm: 1.35
(d, J = 7.0Hz, 6 H), 3.06 (sep, J = 7.0Hz, 1 H), 7.46 (dd, J = 8.1,2.0Hz, 1 H),
7.55–7.58 (m, 2H), 8.62 (d, J = 8.0Hz, 1 H). LC-MS: [M + H]+ m/z 258.
(D5)-Grignard solution (3)
Keeping the inner temperature 64–66 °C, D5-bromobenzene 2 (8.9 g,
55 mmol) dissolved in anhydrous THF (dried over sodium) (20 mL)
was added to a stirred suspension of magnesium filings (2.1 g.
255.29
100
90
80
70
60
50
40
30
20
(1,3-D6)-Propan-2-ol (7)
To a stirred suspension of LiAlH4 (2.5 g, 66 mmol) in diglyme (50 mL, dried
over CaH2) under argon at 0 °C,was slowly added D6-aceton 6 (99.96%
atomD, 10.0 g, 156 mmol). The resulting solution was stirred at 0 °C for
1 h and then diethylene glycol (50 mL) slowly added. The product was
distilled from the reaction mixture, and the fraction boiling between
79–105 °C was collected to give 7 (9.5 g, 144 mmol, 92.3% yield, 99.6%
atomD). 1H NMR (500 MHz, CDCl3) δ ppm: 3.92 (brs, 1H).
276.92
278.26
279.03
10
0
257.10
254.76 258.03
212.95
275.24
210 215 220 225 230 235 240 245 250 255 260 265 270 275 280 285
m/z
Figure 3. MS spectrum of unlabelled 2-isopropylthioxanthone.
J. Label Compd. Radiopharm 2016, 59 313–316
Copyright © 2016 John Wiley & Sons, Ltd.
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C. Fang et al.
was seperated, and the acid layer was further extracted with 100 g of
toluene. The combined organic layers were neutralized with a saturated
sodium carbonate solution, washed with water, dried over anhydrous
magnesium sulfate and concentrated in vacuum. The crude product
was then purified by column chromatography on a silica gel column
using petroleum hexane/ethyl acetate (20:1) as eluent to give 12 (2.2 g,
8.3 mmol, 32.0% yield, 98.8%atomD). 1H NMR (500 MHz, CDCl3) δ ppm:
3.05 (sep, J = 7.0Hz, 1 H), 7.46 (dd, J = 8.1,2.0Hz, 1 H), 7.50–7.51 (m, 2H),
7.55–7.58 (m, 2H), 8.48 (d, J = 2.0Hz, 1 H), 8.61 (d, J = 8.1Hz, 1 H). LC-MS:
[M+H]+ m/z 261.
(1,3-D6)-2-Bromopropane (8)
To a stirred suspension of 7 (9.4 g, 142 mmol) prepared as described
earlier, at À10 °C was added dropwise phosphorus tribromide (24.9 g,
92 mmol). The resulting solution was stirred at room temperature
overnight, and the product 8 is isolated by distillation; the fraction
boiling 50–62 °C was collected (13.2 g, 103 mmol, 72.5% yield, 99.6%
atomD). 1H NMR (500 MHz, CDCl3) δ ppm: 4.24 (s, 1H).
Grignard solution (10)
Keeping the inner temperature at 64–66 °C, bromobenzene 9 (8.6 g,
55 mmol) dissolved in anhydrous THF (dried over sodium) (20 mL) was
added to a stirred suspension of magnesium filings (2.1 g, 88 mmol) in
anhydrous THF (40 mL) over 30 min under N2 atm. The reaction mixture
was stirred under nitrogen at 70 °C for 1 h and then cooled to room
temperature to afford crude 10 which was used in the next step without
further purification.
Conclusions
In summary, two types of stable isotope labelled 2-
isopropylthioxanthone (ITX-D3 and ITX-D6) were prepared with
98.1% and 98.8% isotopic abundance, respectively. The structure
1
was confirmed by H-NMR and LC-MS.
Acknowledgements
(D6)-Isopropylbenzene (11)
A dry and nitrogen-flushed 250 mL two-necked flask, equipped with a
nitrogen inlet and a dropping funnel, was charged with (1,3-D6)-2-
bromopropane 8 (6.4 g, 50 mmol), Co(acae)3 (0.9 g, 2.5 mmol, 5 mol%),
TMEDA (0.29 g, 2.5 mmol, 5 mol%) and anhydrous THF (30 mL). The
reaction mixture was cooled to 0 °C, and then Grignard solution 10
prepared earlier (60 mL, 55 mmol) was added in 2 h. After completion
of the addition, the mixture was stirred to 15 °C for 12 h then quenched
with water (100 mL). The excess solid powder was removed by filtration,
and the filter cake was washed with ether (3 × 50 mL), then the combined
organic layers were dried over anhydrous magnesium sulfate and
concentrated in vacuum. The crude product was then distillated under
reduced pressure (10 mmHg,50–60 °C) to give 11 (5.2 g, 41 mmol, 82%
yield, 99.6% atomD) as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ
ppm: 2.86 (sep, J = 9 Hz, 1H), 7.02-7.29 (m, 5H). GC-MS: m/z 108, 126.
The research was supported by the research grant
(No.2014EG116258 and No.2012BAK25B03-15) from the Ministry
of Science and Technology, P. R. China.
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