Synthesis of isotopically labeled 1,3-dithiane

Article abstract of DOI:10.1002/jlcr.3185

The 1,3-dithiane is a protected formaldehyde anion equivalent that could serve as a useful labeled synthon. We report a facile synthesis of 1,3-[2- ¹³C]- and 1,3-[2-¹³C, 2-²H₂]dithiane in two steps from [¹³

Full text of DOI:10.1002/jlcr.3185

Research Article
Received 30 October 2013,
Revised 22 November 2013,
Accepted 19 December 2013
Published online in 7 February 2014 Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3185
Synthesis of isotopically labeled 1,3-dithiane
b
b
Rodolfo A. Martinez,a,b David R. Glass, Erick G. Ortiz,
*
a
a**
Marc A. Alvarez, and Clifford J. Unkefer
The 1,3-dithiane is a protected formaldehyde anion equivalent that could serve as a useful labeled synthon. We report a facile
synthesis of 1,3-[2-13C]- and 1,3-[2-13C, 2-2H2]dithiane in two steps from [13C]- or [13C, 2H3]methyl phenyl sulfoxide. We have
previously reported the high yield synthesis of [13C]methyl phenyl sulfide from [13C]MEOH and the oxidation of [13C]methyl
phenyl sulfide to [13C]methyl phenyl sulfoxide. Here, we describe the facile exchange of deuterium from 2H2O into [13C]methyl
phenyl sulfoxide to yield [13C, 2H3]methyl phenyl sulfoxide. Thus, from [13C]MEOH and 2H2O, all possible C2 stable
isotopomers of 1,3-dithiane are available. Our synthetic route is also amenable to preparation of radiolabeled 1,3-dithianes.
Keywords: stable isotope labeling; 13C-labeled synthons
Using this route, the overall reported yield from [13C]
Introduction
paraformaldehyde is 51%. From our experience, yields from the
expensive precursor [13C]paraformaldehyde are variable due in
Carbon-13 is enriched from its lighter isotope by cryogenic
distillation of carbon monoxide. Because all labeled carbons
part to the volatility of the intermediates. We have developed a
must be derived ultimately from 13CO, considerable effort has
been devoted to the preparation of useful synthetic precursors
giving rise to efficient large-scale methods for the synthesis of
one-carbon compounds including methane,1 MEOH,2–4 methyl
iodide,4–8 [13C]methyl phenyl sulfide,9 sodium formate,10,11
potassium cyanide,4,12–14 carbon dioxide, carbon disulfide,15
and urea.16 If prepared efficiently, C2-labeled 1,3-dithiane is a
very useful one-carbon donor that allows for the construction
of many useful labeled chemicals and biochemicals.
There are numerous examples for the use of unlabeled 1,
3-dithiane (Scheme 1) for the synthesis of a wide variety of
compounds. The 1,3-dithiane is a protected formaldehyde
equivalent. Lithiated 1,3-dithiane is a ‘formyl anion equivalent’
that has been used extensively in synthetic chemistry.17 For
example, lithiated 1,3-dithiane been added to alkyl halides in
order to produce aldehydes and either symmetrical or
unsymmetrical ketones18–20 as shown in Scheme 2.
new route to 1,3-[2-13C]dithiane from [13C]methylphenyl
sulfoxide that produces less volatile intermediates increasing
the overall yield to 80% (Scheme 5).
Results and discussion
We have previously reported a large-scale and efficient one-pot
synthesis for [13C]methyl phenyl sulfide from [13C]MEOH.9 We
see [13C]methyl phenyl sulfide as a versatile, chemically stable,
and nonvolatile labeling precursor. Here, we report its oxidation
to [13C]methyl phenyl sulfoxide, which serves as a precursor for
the synthesis of 1,3-[2-13C]dithiane. While many conditions have
been used to oxidize sulfides to sulfoxides, we found simply
treating [13C]methyl phenyl sulfide with aqueous hydrogen
peroxide using ethanol as a solvent gave near quantitative yields
of [13C]methyl phenyl sulfoxide. 1,3-[2-13C]Dithiane (1) was
prepared in two steps from [13C]methyl phenyl sulfoxide (2) as
shown in Scheme 5. The Pummerer rearrangement29–31
proceeds quantitatively in the presence of trifluoroacetic
anhydride to yield the mixed thioacetal 3. Heptane is added to
the reaction flask, and the dichloromethane and excess
trifluoroacetic anhydride and trifluoroacetic acid are then
In addition, α-hydroxyketones, β-hydroxyketones, 1,2-diketones,
and α-keto acid derivatives have also been produced from this
protected formaldehyde21,22 (Scheme 3). There are over 1000
references where unlabeled 1,3-dithiane has been used as a
synthetic precursor to synthesize
a variety of important
molecules.23–25 The importance of formyl anion equivalents in
the synthesis of natural products has been reviewed recently.17
While there are numerous examples in the literature where 1,
3-dithiane has been used to make a variety of important synthetic
precursors and biochemicals, isotopically labeled 1,3-dithiane has
seen only limited use26,27 because of the lack of a commercial
source for this important compound. Therefore, the availability of
this new precursor will allow researchers to take advantage of
the wealth of chemistry that has been performed using unlabeled
1,3-dithiane. 1,3-Dithiane is normally made from aqueous
formaldehyde, paraformaldehyde, dialkoxymethane,28 or trioxane.
The example shown in Scheme 4 illustrates the synthesis of 1,
3-[2-13C]dithiane (1) from [13C]paraformaldehyde.27
aBioscience Division, Los Alamos National Laboratory, The National Stable
Isotope Resource, MS E529, Los Alamos, NM 87545, USA
bDepartment of Chemistry, New Mexico Highlands University, Box 9000, Las
Vegas, NM 87701, USA
*Correspondence to: Rodolfo A. Martinez, Department of Chemistry, New Mexico
Highlands University, Box 9000, Las Vegas NM 87701, USA.
E-mail: rudy@nmhu.edu
**Correspondence to: Clifford J. Unkefer, Los Alamos National Laboratory, The
National Stable Isotope Resource, B-11, MS E529, Los Alamos NM 87545, USA.
E-mail: cju@lanl.gov
J. Label Compd. Radiopharm 2014, 57 338–341
Copyright © 2014 John Wiley & Sons, Ltd.

R. A. Martinez et al.
CH3 CH3
H
13C
H
SH
SH
S
H
S
H
O
O
S
S
O
C
13C
MeOH
Reflux
13C
H
H
H
H
1
(75%)
(68%)
Scheme 1. 1,3-Dithiane.
Scheme 4. Synthesis of 1,3-[2-13C]dithiane (1) from [13C]paraformaldehyde.
BuLi
1.BuLi
2. R'-X
R-X
H
H
S
H
S
H
S
H
S
S
H
S
R
S
S
R
O
13C
Li
R'
S
H
Ph TFA
TFAA
S
O
S
S
Deprotect
SH
SH
13C
13C
H
CH2Cl2
H
H
Heptane
H
O
O
2
3
1
H
R
R'
R
NaO2H
2H2O
Scheme 2. Application of 1,3-dithiane in the synthesis of aldehydes and ketones.
Reflux
2H
2H
O
13C
2H
removed by distillation. Propanedithiol is then added to the
reaction flask, and the mixture is refluxed until the reaction is
complete as determined by 13C-NMR spectroscopy. The overall
yield of the carbon-13 label from [13C]MEOH via our synthetic route
of 80% may seem a modest improvement from Baxter and
Abbot’s27 route from [13C]paraformaldehyde (overall yield 51%)
until one considers the cost of the labeled starting material. Based
on current published prices, [13C]paraformaldehyde (~$22.31/
mmol, Cambridge Isotope Laboratories, Inc., Andover MA, USA)
is 4.6-fold more expensive than [13C]MEOH (~$4.83/mmol,
Cambridge Isotope Laboratories, Inc., Andover MA, USA).
Coupled with the overall yields, to prepare a gram of 1,
3-[2-13C]dithiane would require $361 to purchase the precursor
for the paraformaldehyde route and only $50 to purchase the
precursor for our route, which would be particularly attractive
for large-scale synthesis.
S
Ph TFA
S
O
S
S
TFAA
SH
SH
13C
13C
2H
2H
2H
2H
CH2Cl2
Heptane
4
5
6
Scheme 5. Synthesis of 1,3-[2-13C]- and 1,3-[2-2H2, 2-13C]dithiane from [13C]
methyl phenyl sulfoxide.
methyl phenyl sulfide, we have developed a much less expensive
route to the desired deuterated 1,3-dithianes. The methyl
protons in [13C]methyl phenyl sulfoxide (1) are quantitatively
exchanged by heating in deuterium oxide and catalytic sodium
deuteroxide. The [2H3, 13C]methyl phenyl sulfoxide (4) is then
treated as before to yield the 1,3-[2-2H2, 2-13C]dithiane (6) in
high yield. Based on the commercial availability of [14C]
iodomethane and 3H2O, our route could be used to make 1,
3-[2-14C]- or 1,3-[2-14C, 2-3H2]dithiane.
To provide an alternate route to deuterated aldehydes, we
2
have also prepared deuterated 1,3-dithiane. Although [13C, H3]
methyl phenyl sulfoxide (4) can be produced from [13C, 2H3]
S
R
S
α-hydroxyketone
C
OH
Ph
Benzaldehyde
O
CO2
S
R
S
X
R'
S
R
S
C
OH
α-keto acid
1,2-diketone
S
S
C
R'
C
X = Cl, OR
R
Li
O
O
O
R'
S
S
C
β-hydroxyketone
R
HO
R'
Scheme 3. Application of 1,3-dithiane in the synthesis of α-hydroxyketones, β-hydroxyketones, 1,2-diketones, and α-keto acid derivatives.
J. Label Compd. Radiopharm 2014, 57 338–341
Copyright © 2014 John Wiley & Sons, Ltd.
www.jlcr.org

R. A. Martinez et al.
reactivity, attempts at isolation of 3 were not successful. For this reason, 3
was used in the following reaction as a solution in heptane.
Conclusion
In this paper, we have described an efficient synthetic route to
isotopically-labeled 1,3-dithiane. In addition, we have described
the exchange of deuterium into [13C]methyl phenyl sulfoxide.
Thus, both 1,3-[2-13C]-, and 1,3-[2-2H2, 2-13C]dithiane are
synthesized from a single non-volatile starting material, [13C]
methyl phenyl sulfide. An improved preparation of isotopically
labeled 1,3-dithiane will allow for the efficient synthesis of many
useful labeled aldehydes and ketones.
1,3-[2-13C]Dithiane (1)
In a 250 mL oven-dried round bottom flask phenylthio [13C]methyl
trifluoroacetate (17.1 g, 0.072 mol, 1 eq) was dissolved in heptane
(102 mL). The reaction vessel was placed under a reflux condenser
(T = À3°C) under a nitrogen atmosphere. To the stirring solution 1,
3-propanedithiol (7.8 g, 0.072 mol, 1.1 eq) was added in a single portion.
Amberlyst® ion exchange resin (17.1 g, 1:1 wt ratio of labeled starting
material) was added as a solid through a powder funnel. The reaction
flask was placed into a heating mantle (T = 135°C) and allowed to reflux.
Product formation was monitored by 13C-NMR noting the disappearance of
(phenylthio)[13C]methyl trifluoroacetate (δ = 73 ppm) and the subsequent
appearance of the desired 1,3-[2-13C]dithiane (δ = 32ppm) The reaction
was judged to be complete after 18h. The hot reaction mixture was filtered
quickly using vacuum and a Büchner funnel to remove the Amberlyst®
resin. Heptane (50mL) was removed by simple distillation to leave the
product in 52mL heptane (6mL/gram of 1). The reaction mixture was
allowed to cool to room temperature and then washed with 1 M aqueous
sodium hydroxide (50 mL). The aqueous layer was then extracted with
heptane (100mL). The combined organic layers were cooled in a freezer
at À19°C for 1 h and filtered to yield 1 as colorless crystals. Pentane
(15mL) was added to the filtrate and the mixture placed back into the
freezer, where more of compound 1 crystallized and was recovered by
filtration. The crystals were combined to obtain 1,3-[2-13C]dithiane (1)
(7.0g, 80%) having an m.p. range of 52–54°C. 1H-NMR (CDCl3, 300 MHz):
δ = 2.08 (m, 2H), 2.84 (m, 4H), 3.79 (d, 2H, 1JCH = 149.6Hz). 13C-NMR (CDCl3,
Experimental
General
[
13C]Carbon monoxide and [13C]carbon dioxide enriched to 99.2% were
supplied by the Los Alamos ICONS facility. [13C]MEOH2,3 and [13C]methyl
phenyl sulfide9 were prepared by the National Stable Isotope Resource at
Los Alamos using published methods. All other chemicals were
purchased from commercial sources as reagent grade and used without
purification. Proton-decoupled 13C (75 MHz) and 1H (300 MHz) NMR
spectra were obtained at 25°C at using a Bruker DRX-300 NMR
spectrometer. Samples were dissolved in CDCl3 and the resonance signal
from CDCl3 (13C, 77.23 ppm) or CHCl3 (1H, 7.27 ppm) used as an internal
chemical shift standard. Proton-decoupled13C-NMR specta were used to
determine the extent of deuteration in [13C, 2H3]methyl phenyl sulfoxide.
To minimize the effects of NOE and differences in T1 between protonated
and deuterated species, the 1H-decoupler was turned off during a 60 s
delay between pulses.
2
3
75MHz): δ = 26.6 (d, JCC = 2.8 Hz, CH2CH2S13CH2), 29.9 (d, JCC = 1.1Hz,
CH2CH2S13CH2), 31.9 (s, S13CH2S). Elemental analysis of 1: Calculated:
13CC3H8S2: C, 40.45; H, 6.65; S, 52.90. Found: C, 40.45; H, 6.51; S, 52.90.
[13C]Methyl phenyl sulfoxide (2)
In a 1-L round bottom flask [13C]methyl phenyl sulfide (10.0 g, 77.6 mmol,
1 eq) was dissolved in ethanol (50 mL). The solution was cooled in an ice-
water bath. Hydrogen peroxide (30% by mass, 23.8 g, 7.92 g, 233 mmol,
3 eq) was added dropwise via addition funnel. The reaction was
permitted to stir at room temperature. The reaction was monitored by
13C-NMR following the disappearance of [13C]methyl phenyl sulfide
(δ = 16 ppm) and appearance of the desired [13C]methyl phenyl sulfoxide
(δ = 44 ppm). After 24 h, the reaction was complete. The reaction mixture
was then transferred to a 1-L Erlenmeyer flask containing dichloromethane
(100mL) and cooled in an ice/water bath. Remaining H2O2 was
decomposed by dropwise addition of aqueous sodium bisulfite (15%) until
oxidant was no longer visualized using potassium iodide/starch paper. The
layers were separated, and the organic layer was dried with sodium sulfate
and then vacuum filtered. The volatiles were removed using a rotary
evaporator followed by evacuation under reduced pressure to constant
weight. Compound 2 was recovered as a colorless solid (11.0g, 99% yield)
that was used without further purification. 1H-NMR (CDCl3, 300 MHz):
[2H3, 13C]Methyl phenyl sulfoxide (4)
A 100-mL round bottom reaction flask was equipped with a magnetic stir
2
bar, filled with H2O, and stoppered. After stirring overnight, the round-
bottom flask was then emptied, flushed with argon, then 2H2O (30 mL,
99% 2H) was added, stirring under an argon atmosphere. The [13C]methyl
phenyl sulfoxide (2) (1.52 g, 10.8 mmol, 1 eq) was added to the 2H2O,
forming a heterogeneous mixture. An air-cooled reflux condenser was
fixed to the reaction flask and the reaction mixture, and placed in an
argon atmosphere. Sodium deuteroxide (0.22 g, 40% in D2O, 2.2 mmol,
0.20 eq) was added via syringe. The reaction mixture was then placed
into a heating mantle, and refluxed for 4 h. As the reaction mixture came
to reflux, it became homogeneous. After heating at reflux for 4 h, the
reaction mixture was cooled and extracted with dichloromethane (3x,
15 mL). The organic layers were combined and dried using sodium
sulfate, filtered, and then volatiles were removed by vacuum using a
rotary evaporator to yield 4 as a light tan oil (1.53 g, 99%); 13C NMR analysis
showed >99% deuterium incorporation into 4. The resulting product was
1
δ = 2.73 (d, 3H, JCH = 139.6 Hz), 7.44–7.75 (m, 5H). 13C-NMR (CDCl3,
75 MHz): δ = 44.3 (13CH3), 123.8, 129.7, 131.3, 146.0.
1
used without further purification. H-NMR (CDCl3, 300 MHz): δ = 7.45–7.81
(m, 5H). 13C-NMR (CDCl3, 75 MHz): δ = 43.2 (septet, JCD = 21.2 Hz, 13CD3),
1
(Phenylthio) [13C]methyl 2,2,2-trifluoroacetate (3)
123.6, 129.4, 131.1, 145.6.
In a 500-mL oven-dried round bottom flask [13C]methyl phenyl sulfoxide
(18.0 g, 0.125 mol, 1.0 eq) was dissolved in dichloromethane (181 mL).
The reaction vessel was flushed with argon and was cooled using an ice-
water bath. After the solution had stirred for 60 min, the internal
temperature of the solution was 4°C. Trifluoroacetic anhydride (210 g,
1.0mol, 8.0 eq) was added via syringe to the stirring solution. Product
formation was monitored by 13C-NMR noting the disappearance of [13C]
methyl phenyl sulfoxide (δ = 44 ppm) and appearance of (phenylthio)[13C]
methyl trifluoroacetate (δ = 73 ppm). The reaction was judged to be
complete after 2.5 h. Heptane (93 mL) was then added to the reaction
(Phenylthio) [2H2, 13C]methyl 2,2,2-trifluoroacetate (5)
(Phenylthio)[13C, 2H2]methyl trifluoroacetate (5) was prepared from [13C,
2H3]methyl phenyl sulfoxide (1.53 g, 0.011 mol) using the same
procedure reported for 3. Because of its reactivity, attempts at isolation
of 5 were not successful. For this reason, 5 was used in the following
reaction as a solution in heptane.
1,3-[2-2H2, 2-13C]Dithiane (6)
mixture. The reaction vessel was covered with an air-cooled reflux 1,3-[2-2H2, 2-13C]Dithiane (6) was prepared from (phenylthio)[2H2, 13C]
condenser and placed into a heating mantle. A simple distillation apparatus methyl trifluoroacetate (5) (2.54 g 0.011 mol) using the same procedure
was placed above the air-cooled reflux condenser. The reaction was and with comparable yields reported previously for 1. 1H-NMR (CDCl3,
refluxed for 4.5h, until the dichloromethane and trifluoroacetic anhydride 300 MHz): δ = 2.08 (m, 2H), 2.83 (m, 4H). 13C-NMR (CDCl3, 75 MHz):
and acid were distilled away from the reaction solution. Because of its δ = 26.7 (d, JCC = 2.8 Hz, CH2CH2S13CD2), 29.9 (s, CH2CH2S13CH2), 31.6
2
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J. Label Compd. Radiopharm 2014, 57 338–341

R. A. Martinez et al.
1
(pentet, JCD = 22.9 Hz, S13CD2S). Elemental analysis of 6: Calculated:
[9] R. A. Martinez, M. A. Alvarez, S. P. Velarde, L. A. P. Silks, P. L. Stotter, J.
G. Schmidt, C. J. Unkefer, Org. Process Res. Dev. 2002, 6, 851.
[10] B. D. Andresen, J. Org. Chem. 1977, 42, 2790.
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[12] D. G. Ott, V. N. Kerr, T. G. Sanchez, T. W. Whaley, J. Label. Compd.
Radiopharm. 1980, 17, 255.
13CC23H2H6S2: C, 39.80; H, 8.15; S, 52.05. Found: C, 39.69; H, 8.11; S, 51.92.
Acknowledgements
This work was funded in part by the National Stable Isotope
Resource at the Los Alamos National Laboratory (NIH grant award
P41RR02231) and by the New Mexico Highlands University.
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Conflict of Interest
The authors did not report any conflict of interest.
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