Dithiolopyranthione synthesis, spectroscopy, and an unusual reactivity with DDQ

Article abstract of DOI:10.1002/jhet.1715

The pyranodithiolone rearranges to a more stable isomer and the pyran ring opens up in the presence of DDQ. The bicyclic pyran thiolone tetrahydro-3αH-[1,3]dithiolo[4,5-β]pyran-2-thione (3a) engages in a highly unusual fragmentation in the presence of DDQ

Full text of DOI:10.1002/jhet.1715

July 2013
Dithiolopyranthione Synthesis, Spectroscopy, and an Unusual Reactivity
with DDQ
879
Igor V. Pimkov,a Archana Nigam,a Kiran Venna,a Fraser F. Fleming,a Pavlo V. Solntsev,b Victor N. Nemykin,b and
a
*
Partha Basu
aDepartment of Chemistry and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania 15282
bDepartment of Chemistry, The University of Minnesota-Duluth, Duluth, Minnesota 55812
*
E-mail: Basu@duq.edu
Additional Supporting Information may be found in the online version of this article.
Received January 4, 2012
DOI 10.1002/jhet.1715
Published online 1 July 2013 in Wiley Online Library (wileyonlinelibrary.com).
The bicyclic pyran thiolone tetrahydro-3aH-[1,3]dithiolo[4,5-b]pyran-2-thione (3a) engages in a highly
unusual fragmentation in the presence of DDQ. The pyran thiolone, 3a, was synthesized by chlorination
of 3,4-dihydro-2H-pyran (1) followed by condensing with CS2 and NaSH. Reaction of 3a with DDQ
generates the isomerized pyran thiolone tetrahydro-3aH-[1,3]dithiolo[4,5-b]pyran-2-thione (3b) and
4-benzyl-5-(3-hydroxypropyl)-1,3-dithiole-2-thione (4) via a deep-seated rearrangement. The identity
of 3b was confirmed by single crystal X-ray analysis: P21/c, a = 5.807(9) Å, b = 12.99(2) Å,
c = 11.445(15), b = 113.23(6)ꢀ. Mechanistic experiments and computational insight is used to explain
the likely sequence of events in the highly unusual formation of 4. Collectively, these results establish
fundamental reactivity patterns for further research in this area.
J. Heterocyclic Chem., 50, 879 (2013).
INTRODUCTION
open form exposing an alcohol [23,24]. In fact, the open
pyran ring was initially thought to be the structure of the
cofactor. In some cases, the metal ion is coordinated by
endogenous ligands such as serine in DMSO reductase or
cysteine in nitrate reductase [25]. Critical to understanding
the basic chemistry of such systems is the ability to synthe-
size dithiolenes coupled with other molecular entities. We
have been engaged in the design and synthesis of new
pyranopterin dithiolenes as a part of our program to understand
the structure–function relation of pyranopterin containing
enzymes [18,24,26,27].
The importance of 1,2-dithiolenes has stimulated several
syntheses. An established method of preparing an arene
dithiolene is the reductive dealkylation of 1,2-C6H4(SR)2
[28,29], or alternatively through directed lithiation of
thiphenols followed by electrophilic addition [30]. Substitu-
tion on benzene rings provides an entry to different functiona-
lized dithiolene derivatives [26,31]. 1,2-Alkene dithiolenes
are generally prepared as salts or as latent precursors that
can be deprotected before ligation to a metal ion. For example,
the disodium salt of dimercapto maleonitrile has been synthe-
sized by reacting CS2 with NaCN. [32] The syntheses of
The chemistry of vinyl disulfides, also known as
dithiolenes (S–C═C–S), is as vast as it is transformative.
Dithiolenes have a particularly rich coordination chemistry
[1–4] with potential applications in material science [5,6],
whereas their incorporation within organic metals afford
superconducting materials. Dithiolenes have distinctive
redox and structural features [7–12] that have shown promise
as potential sensor materials with unparalleled optical and
magnetic properties. [5,13–16] The luminescent properties
of these dithiolene complexes have been used in developing
sensors for molecular oxygen, [17] and the fluorescence
properties have been utilized in developing sensors for metal
ions such as Pb2+ [18]. Dithiolene-based catalysts have also
been used for separations of olefins [19].
The basic dithiolene unit is recognized to be at the heart
of more than 50 molybdenum and tungsten enzymes
[20,21]. These enzymes catalyze a wide variety of
reactions that constitute important processes in all phyla
of life including humans [22]. Here, the dithiolene ligand
comprises a part of a more complicated three ring pterin
cofactor, where the third pyran ring exists at times in an
© 2013 HeteroCorporation

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I. V. Pimkov, A. Nigam, K. Venna, F. F. Fleming, P. V. Solntsev, V. N. Nemykin, and P. Basu
Vol 50
(2) as a yellow liquid. The product was isolated as a
mixture of isomers (~34 g, 91%) exhibiting identical
spectra to that reported previously [36,37]. In non-polar
solvents, the cis-isomer is the major product, whereas in
polar solvents, the trans-isomer is the major product [36].
The trans isomer exists in a conformation with two
equatorial chlorines; the axial–axial splitting is ~10 Hz in
the H NMR spectrum [38]. On the basis of the NMR
spectra, the cis isomers and the trans isomer are present
in a ~55:45 ratio [36].
protected 1,2-dithiolene is expediently achieved by treating
a-haloketones with a xanthate salt followed by an acid
catalyzed cyclization [33,34].
Synthetic strategies for accessing pyranodithiolene are
less developed, and even less is known about the condi-
tions pyran ring opening [35]. A conceptually attractive
strategy for preparing pyranodithiolenes is to sulfurize a
pyran ring followed by dehydrogenation to form a carbon–
carbon double bond to the target compound. Herein, we report
reactions of 1,2-dichloro-pyran with thionodithio carbonate as
a bis-sulfur nucleophile, stereoselectively forming the
tetrahydropyran dithiolane 6. Subsequent dehydrogenation
of 6 with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ),
affords a highly unusual product in which the pyran ring is
cleaved accompanied by isomerization to a diastereoisomer
via a deep-seated rearrangement. In addition to disclosing
the synthetic details, we report characterization and provide
a plausible mechanism to account for the highly unusual mo-
lecular transformation.
1
Nucleophilic substitution of chlorine with sulfur. Reaction
of 2 with a sulfide nucleophile such as CS2/NaSH or Na2S in
DMF leads to the formation of carbon–sulfur bonds at the
expense of carbon–chlorine bonds [39]. In the present case,
CS2/NaSH provided 3a in 25% overall yield. Only the
cis-isomer can afford 3a in a stereoselective reaction
reducing the overall yield of the compound. We anticipate
that the reaction proceeds through an initial attack by a
sulfur from the trithiocarbonate nucleophile replacing the
chlorine at position 2. A second nucleophilic attack at
position 3 by the second sulfur of the trithiocarbonate
completes the cycloaddition reaction. The cis-isomer is
energetically more favorable in this stereoselective reaction.
The 1H NMR spectrum of 3a shows a doublet at
4.73 ppm assigned to H2 (Table 1); the 10.5 Hz coupling
RESULTS
Chlorination of 3,4-dihydropyran. Chlorination of 3,4-
dihydro-2H-pyran (1) [36,37] was conducted in dry
pentane at À78 ꢀC to yield 2,3-dichlorotetrahydropyran
Table 1
Room temperature NMR data for compound 3a collected in C6D6.
Cross peaks
in HMQC
Position
13C, d, ppm
Position
1H d, ppm
J, Hz
Cross peaks in COSY
C2
C3
C6
C6
C4
C5
C4
C5
C7
94.66
60.47
69.19
69.19
26.49
24.86
26.49
24.86
220.36
H2 (ax)
H3 (ax)
H6 (eq)
H6 (ax)
H4 (eq)
H5 (eq)
H4 (ax)
H5 (ax)
4.73 (d)
3.52 (ddd)
10.5
H3 (ax)
H2 (ax), H4 (ax), H4 (eq)
H6 (ax), H5 (eq), H5 (ax)
H6 (eq), H5 (eq), H5 (ax)
H3 (ax), H4 (ax), H5 (ax), H5 (eq)
H6 (eq), H6 (ax), H4 (eq), H4 (ax), H5 (ax)
H3 (ax), H4 (eq), H5 (ax), H5 (eq)
H6 (eq), H6 (ax), H4 (eq), H4 (ax),H5 (eq)
H2 (ax)
H3 (ax)
10.5, 12, 3.5
11.5, 5, 1.5, 1.5
12, 12, 3
3.45 (dddd)
2.78 (ddd)
1.17–1.22 (m)
0.96–1.06 (m)
0.88–0.95 (m)
0.72–0.76 (m)
H6 (eq), H6 (ax)
H6 (eq), H6 (ax)
H4 (eq), H4 (ax)
H5 (eq), H5 (ax)
H4 (eq), H4 (ax)
H5 (eq), H5 (ax)
Table 2
Room temperature NMR data for compound 3b in C6D6.
Position
13C, d, ppm Position
1H d, ppm
J, Hz
Cross peaks in COSY
Cross peaks in HMQC
C2
C6
C3
C6
C4
C5
93.83
65.25
57.77
65.25
24.81
21.51
H2 (eq/ax)
H6 (eq)
H3 (eq/ax)
H6 (ax)
H4 (eq)
H5 (eq)
5.18 (d)
3.45 (ddd)
3.35(ddd)
2.94 (ddd)
1.32–1.41 (m)
1.19–1.26 (m)
4
H3 (eq/ax)
H2 (eq/ax)
H6 (eq), H6 (ax),
H3 (eq/ax)
H6 (eq), H6 (ax),
H4 (eq), H4 (ax)
H5 (eq), H5 (ax)
11, 7, 3
6.5, 4.5, 4.5
11, 7.5, 3
H6 (ax), H5 (ax), H5(eq)
H2 (eq/ax), H4 (eq), H4 (ax)
H6 (eq), H5 (eq), H5 (ax)
H4 (ax), H5 (ax), H5 (eq), H3 (eq/ax)
H5 (ax), H6 (ax), H6 (eq),
H4 (eq), H4 (ax)
C4
C5
24.81
21.51
H4 (ax)
H5 (ax)
1.07–1.13 (m)
0.75–0.82 (m)
H4 (eq), H3 (eq/ax), H5 (eq), H5 (ax)
H5 (eq), H6 (eq), H6 (ax), H4 (eq),
H4 (ax)
H4 (eq), H4 (ax)
H5 (eq), H5 (ax)
C7
224.93
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Dithiolopyranthione Synthesis, Spectroscopy, and an Unusual Reactivity with DDQ
881
with H3 (vide infra) suggests that both are in an axial
orientation. Single frequency decoupling and COSY experi-
ments of H3 (d = 3.52 , ddd) are consistent with this
assignment. The two large couplings (11 Hz) of H3 are due
to two axial–axial couplings assigned to H2 and H4, and
the smaller coupling of 4 Hz is due to an axial–equatorial
coupling. Collectively, the results are consistent with axial
orientations of H2 and H3. Peaks at 2.78 ppm (ddd) and
3.45 ppm (dddd) are assigned to the axial and equatorial
protons at C6 (H6ax and H6eq, respectively). The remaining
four sets of multiplets in the upfield region are assigned to the
four protons H4ax/H4eq and H5ax/H5eq, consistent with
correlation and decoupling experiments.
A distinct resonance at 220.36 ppm in the 13C NMR spec-
trum is assigned to the thione group, and the resonance at
94.66 ppm is assigned to C2, which is attached to two
electronegative atoms. Resonances at 69.19 and 60.47ppm
are assigned to carbons C3 and C6, respectively, whereas
the resonances at 26.49 and 24.86 ppm are assigned to C4
and C5, respectively. The infrared spectrum of 3a has a
diagnostic signal at 1093 cmÀ1 for the C═S stretch.
Conversion of thione (3a) to ketone (5). Conversion of
the thione (3a) to ketone (5) occurred smoothly under
standard conditions. The spectral data for 5 were very
similar to those of 3a as expected for sulfur to oxygen
interchange. However, the carbonyl carbon of 5 resonates
at 189.36 ppm, ~30 ppm upfield from that of 3a. The
C═S stretch of 3a that appeared at ~1093 cmÀ1 was
replaced by C=O stretch at ~1720 cmÀ1 in 5. The GC–MS
showed a [M + H]+ peak at 177 m/z with the isotope
1
Figure 1. Room temperature H NMR spectra of compound 3a (A) and
compound 3b (B) in C6D6. The expanded sections are shown in the insets.
Assignments of the peaks are tabulated in Tables 1 and 2.
and the molecular ion peak ([M + H]+, 283.0282 m/z) in
the high resolution mass spectrum.
distribution identical to the theoretical pattern.
Reaction of 3a with 2,3 dichloro 5,6-dicyano quinone.
The 13C NMR spectra of 3a and 3b are very similar;
however, the 1H NMR spectra differ in their chemical shift
as well as splitting pattern (Fig. 1). The H2 resonance is
shifted downfield from 4.73 ppm in 3a to 5.18 ppm (d) in
3b (Table 2). The large (10.5 Hz) coupling in 3a indicates
axial orientations of both H2 and H3, whereas the smaller
coupling (4.0 Hz) constant in 3b suggests an axial–equatorial
interaction, which is consistent with the solid state structure.
In order to understand whether the molecule is fluxional,
Exposing 3a to DDQ in toluene afforded dithiole-2-
thione 4 (10% yield) and thione diastereoisomers 3a
(65%) and 3b (22%). The spectroscopic data clearly
established the structure of 4 (Scheme 1). Particularly,
diagnostic was the 13C resonance due to the C═S at
1
227 ppm, the benzylic H NMR resonance at 4.8 ppm,
Scheme 1
1
the H NMR spectrum of 3b in acetone was recorded
at 180 K giving broad singlet peaks at 5.96 ppm and
5.03 ppm, respectively, for H2 and H3. In the same
solvent, at room temperature, these resonances appear at
6.18 ppm (d, J ~ 3.8 Hz) and 4.79 ppm (ddd, 6.2, 4.2,
4.8 Hz), respectively, for protons H2 and H3. Thus, the
signal for H2 (d = 5.18) moved upfield whereas that for
H3 moved downfield. We suggest that even at 180 K in
acetone, a dynamic environment exists and the broadening
of the peaks is due to an increase in viscosity and the
compound’s dynamic behavior.
In order to understand the driving force for rearrange-
ment of compound 3a into compound 3b in the reaction
with DDQ, DFT calculations were conducted at the
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I. V. Pimkov, A. Nigam, K. Venna, F. F. Fleming, P. V. Solntsev, V. N. Nemykin, and P. Basu
Vol 50
B3LYP/6-311+G(d) level (details are in the supporting
information). Such a level of theory has provided reliable
geometries, energies, and spectroscopic properties of sulfur
containing thiols, disulfides, thiones, and thioamides
[26,40–54]. The DFT structure is very similar to that deter-
mined by crystallographically, although the bond distances
are longer (Table 3). We suggest that longer distances are
due to the disorder in the crystal structure that required
constraints, as well as the relaxed nature of the calculated
structure in the gas phase. Compound 3b was 1.84 kcal
(2.03 kcal with zero-point energy correction) more stable
than thione 3a. We suggest that the increased stability of
3b is due to the cis-fusion of the two rings that relieves
the torsional strain in the trans thione 3a (Fig. 2), similar
to the reported steric strain in the all carbon system [55].
This steric strain is reflected in the bond angles. The
<S(3)CC bond angles calculated from the optimized struc-
tures are: <SC3C2, 107.7ꢀ; <SC3C4, 112.6ꢀ for 3b, and
106.1ꢀ and 116.4ꢀ for the same angles in 3a. Deviations from
the idealized tetrahedral nature of the bridgehead carbon in
3a impart strain making 3a less stable than 3b. Equilibration
Figure 2. Calculated structures of 3a (left) and 3b (right) differing in
S–C–C bond angle (see text).
Figure 3. Thermal ellipsoid diagram (50% probability) of the R,R-3b.
fragment is essentially planar, whereas the five-membered C1–
S2a–C2a–C3a–S3a heterocyclic moiety adopts a twist
conformation. Specifically, large torsion angles for C(1)–S
(2A)–C(2A)–C(3A) fragment (34.4(6)ꢀ) and C(1)–S(3A)–C
(3A)–C(2A) fragment (31.1(6)ꢀ) exclude more a common
“envelope” conformation.
would therefore favor 3b over 3a.
Crystal structure of 3b. The unit cell of 7-dihydro-5H-
[1,3]dithiolo[4,5-b]pyran-2-thione (3b) contains (R,R) and
(S,S) enantiomers. The molecular structure of (R,R) 3
is shown in Figure 3, whereas selected geometric
parameters are listed in Table 3. The bicyclic structure of
3b is evident with the six and five-membered rings
connected by a common single (C2a–C3a) bond. Although
saturated five-membered [1,3]dithiolo-2-thione heterocycles
connected via a single carbon–carbon bridge to saturated
six-membered rings are known, the crystal structure is not.
A search of the Cambridge Crystallographic Structure
Database [56] indicates that dithione 3b is the only example
of such a bicyclic motif. The C═S double bond is
significantly shorter (1.602(3) Å) than that reported in a
related compound (1.657 Å) [57], whereas the C─S single
bonds (1.790(6) Å, 1.730(4) Å) are close to those reported
for similar thiones [58]. The six membered pyran ring adopts
a typical "chair" conformation, the [1,3]-dithiolo-2-thione
DISCUSSION
The chlorination of 1 and the subsequent sulfurization
smoothly provide dithione 3a (Scheme 1) [39]. Extrusion
of oxygen using mercuric acetate and acid, quantitatively
converts thioketone 3a to ketone 5, following the proce-
dure for preparing dithiocarbonate ligands [18]. Treating
3a with DDQ causes a deep-seated rearrangement to 3b
that is highly unusual. Control experiments demonstrate
the requirement of DDQ, which presumably triggers the re-
action through a sequence of proton and electron transfers
[59–61]. Mechanistically, single electron transfer from
toluene to DDQ and loss of a proton would yield a
Table 3
Selected bond distances (Å) and angles (ꢀ) for 3b from X-ray structure and those obtained from the DFT calculation are in parenthesis [].
S1–C1
1.602(3)
[1.638]
C1–S2a–C2a
95.8(3)
[97.31]
S2a–C1
S2a–C2a
S3a–C1
S3a–C3a
C2a–O1a
C2a–C3a
C3a–C4a
C4a–C5a
C5a–C6a
C6a–O1a
1.730(4)
1.755(7)
1.642(3)
1.790(6)
1.380(8)
1.473(8)
1.480(8)
1.475(14)
1.478(10)
1.418(13)
[1.773]
[1.826]
[1.762]
[1.847]
[1.408]
[1.536]
[1.537]
[1.533]
[1.524]
[1.433]
C1–S3a–C3a
O1a–C2a–C3a
O1a–C2a–S2a
C3a–C2a–S2a
C2a–C3a–S3a
C4a–C3a–S3a
C2a–O1a–C6a
S1–C1–S3a
97.9(3)
112.6(6)
107.3(5)
108.6(5)
107.0(5)
112.3(5)
113.4(7)
127.7(2)
117.7(2)
114.6(2)
[97.19]
[113.67]
[108.1]
[108.14]
[107.72]
[112.59]
[113.21]
[123.72]
[122.67]
[113.61]
S1–C1–S2a
S3a–C1–S2a
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Dithiolopyranthione Synthesis, Spectroscopy, and an Unusual Reactivity with DDQ
883
relatively stable benzyl radical (Scheme 2). Protonation of the
pyran oxygen in 3a likely generates oxonium ion (6) that trig-
gers the pyran ring opening, analogous to the proposed pyran
ring of opening in the pyranopterin cofactor [62]. The result-
ing sulfenyl cation 7 could eliminate proton to form 8 (path a,
Scheme 2) or recyclize by attack of the alcohol on the more
accessible a-face leading to 3b (path b, Scheme 2). The
preferential formation of 3b is consistent with the greater
calculated stability of 3b over 3a. Subjecting 3a to formic
acid in refluxing toluene generates 3b with 30% conversion,
consistent with a slow equilibrium from 3a to 3b.
reduced form of DDQ. Consistent with this mechanistic
scenario, when the reaction was conducted in deuterated
toluene, isotope enrichment was only observed in the benzyl
functionality of 4. The deuterium labeling experiment
demonstrates the incorporation of solvent and indirectly
supports an initial deuterium abstraction by DDQ.
Consistent with the key role of hydroxy dithione, 8,
exposing 3a to p-toluenesulfonic acid in refluxing toluene
affords the tosylate 12. Presumably, protonation of 3a
generates 8 that subsequently protonates to afford 10 that
then cyclizes to afford sulfenyl cation 11 (Scheme 1).
Opening of the thiophene ring by nucleophilic attack of
the tosylate yields 12. Trapping the tosylate 12 under these
conditions provides supports for the presence of 8 in the
rearrangement mechanism.
A likely intermediate in this sequence is the hydroxy-
dithione, 8. In acidic media, 8 can equilibrate to 3a and
3b but in the presence of DDQ the benzyl radical intercepts
8 to form sulfur-stabilized radical 9. Subsequent hydrogen
•
atom abstraction by DDQH would afford 4 and the
SUMMARY
Scheme 2
DDQ triggers a highly unusual rearrangement of the
pyran dithiolate 3a. Although 3a is readily prepared, no
unusual rearrangements or isomerizations have been
reported for this type of substrate. A series of mechanistic
probes provides strong evidence for an equilibrium radical
trapping sequence. Refluxing 3a in formic acid equilibrates
the trans-fused pyran dithiolate 3a to the corresponding
cis-fused pyran dithiolate, 3b. In the presence of DDQ, the
ring opening is accompanied by formation of a benzylic
radical capable of trapping the hydroxy dithione 8 to ulti-
mately afford 4. Using deuterium labeled toluene leads to
incorporation of a deuterated benzylic group with no addi-
tional deuterium label. Collectively, these mechanistic experi-
ments provide insight into pyran ring opening and closing
reactions of potentially general relevance for pterin-containing
molybdenum enzymes during catalytic turnover [62].
EXPERIMENTAL
Materials and instrumentation.
The chemicals were
purchased from Aldrich Chemical Company or ACROS Chemical
Company and were used without further purification. Commercial
grade solvents were dried and purified using a solvent purification
system (SP-105) by LC Technology Solutions Inc. before use.
Toluene was dried and distilled over Na-benzophenone,
chloroform and pentane were dried and distilled over CaH2. NMR
spectra were collected on Bruker ACP-300, Bruker Avance 400, or
500 and Varian Unity 500 spectrometers. Mass spectra were
obtained with a Waters LCQ ESI/APCI. High resolution mass
spectra (HRMS) were collected on an Agilent 6200 time of flight
LC MS system using a nano ESI–TOF interface. IR spectra were
recorded either on a Perkin-Elmer FT-IR 1760X spectrometer or a
Nicolet 380 FTIR (Thermo) spectrometer. Melting points were
determined on a Mel-Temp II apparatus. GC–MS were recorded
on a Varian Saturn II instrument.
Scheme 3
Synthesis.
Synthesis of 2,3-dichlorotetrahydro-2H-pyran (2).
A
Schlenk flask was charged with 3,4-dihydro-2H-pyran, (1),
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The reaction of 3a with DDQ in toluene-d8. A dry toluene-
d8 solution (2 mL) of tetrahydro-3aH-[4,5-b]pyran-2-thione (3a)
(0.015 g, 0.078 mmol) and DDQ (0.022 g 0.097 mmol) was
refluxed for 53 h. The reaction was monitored by thin layer
chromatography (silica, dichloromethane-hexane: 2:1); and
purified by preparative TLC (silica, dichloromethane/hexanes:
2:1). The first yellow fraction is isotopically labeled 4 (or 4a);
compound 3a and 3b eluted as the second and third fractions,
respectively. Yields were not calculated.
(20 g, 238 mmol) and pentane (65 mL) under an Ar-atmosphere. The
contents were cooled to À78 ꢀC using an acetone-dry ice bath and
using Teflon tubing, chlorine gas was slowly bubbled through the
solution with stirring until a yellow color persisted (~25 min).
Chlorine gas was then passed for an additional 10 min to ensure
completion of the reaction. Argon gas was then bubbled through
the solution to remove excess chlorine gas, and then the solvent
was removed under reduced pressure. The resulting colorless liquid
was purified by distillation at ~55 ꢀC (~30 mmHg) to yield 2 as a
colorless liquid. Yield: 92% (33.9 g, 219 mmol).
1
Characterization of 4a. H NMR (CDCl3), d, ppm: 2.01 (qd,
1H NMR (C6D6) d, ppm: 0.84 (d, 1H, 13 Hz), 1.04 (d, 1H,
13 Hz,) 1.16–1.25 (m, 1H), 1.45 (d, 1H, 14 Hz), 1.53 (d, 1H,
12 Hz), 1.85–1.99 (m, 2H), 2.06–2.12 (m, 1H), 3.23–3.26
(m, 1H), 3.40 (dd, 1H, 11 Hz, 4.5 Hz), 3.60–3.62 (m, 1H), 3.67
(qd, 2H 3 Hz, 1 Hz), 3.84(s, 1H), 5.87 (d, 1H, 3 Hz), 5.93
(s, 1H). 13C NMR (C6D6) d, ppm: 19.00, 24.92 (C4) 25.60,
27.75 (C5) 57.68, 58.20 (C3), 60.75, 61.99 (C6), 94.42, 96.47
(C2); ESI MS+ (m/z): 119 (calculated for C5H8ClO [M À Cl]+,
119); IR (neat), cmÀ1: 2949, 2929, 2876, 1070, 976, 874, 436.
Synthesis of tetrahydro-3aH-[1,3]dithiolo[4,5-b]pyran-2-
thione (3a). Sodium hydrosulfide hydrate (1.10 g, 19.69 mmol)
was dissolved in DMF (15 mL) and neat carbon disulfide
(1.49 g, 19.69 mmol) was added at room temperature over
30 min. The mixture was then warmed to 40 ꢀC. A DMF solution
(2 mL) of 2,3-dichloropyran (2) (2 g, 13.00 mmol) was added to the
reaction mixture. After 2 h, water (100 mL) and then chloroform
(75 mL) were added, and then the target compound was extracted
with chloroform and dried over anhydrous Na2SO4. Evaporation of
the organic phase afforded a yellow colored liquid, which was
purified by silica gel column chromatography (hexanes/chloroform,
2:1). The first yellow band was collected and evaporated to yield
3a as a yellow solid, mp: 73–74 ꢀC. Yield 25% (0.61g,
3.21mmol). NMR data are presented in Table 1. IR (KBr): 1093
(C═S) 1084cmÀ1; IR (neat), cmÀ1: 2945, 2917, 2847, 1442,
1082, 1046, 1021, 477; HRMS ESI+ (m/z): 192.9812 [calculated
for C6H9S3O (M+ H+), 192.9810]; (GC–MS): 191.8 (calculated
for C6H8S3O (M+) 192); HRMS ESI+ with 0.1% HCOOH (m/z):
190.9651 (calculated for C6H8S3O (M À 2H+ H+), 190.9659).
Synthesis of 4-benzyl-5-(3-hydroxypropyl)-1,3-dithiole-2-
thione (4) and tetrahydro-3aH-[1,3]dithiolo[4,5-b]pyran-2-thione
(3b). A toluene solution (10 mL) of tetrahydro-3aH-[1,3]dithiolo
[4,5-b]pyran-2-thione (3a) (0.17 g, 0.88 mmol) in dry and DDQ
(0.22 g, 0.975 mmol) was heated to reflux for 48 h. The reaction was
then cooled, the solvent was removed, and then the crude product
was purified by silica gel chromatography (hexanes/chloroform, 2:1)
to afford 24 mg (0.08 mmol, 10%) of 4 as an oily liquid; 110 mg
(65%) of 3a, and 37 mg (22%) of 3b as a crystalline solid.
2H, 6.3 Hz, 10.5 Hz), 2.36 (td, 2H, 1.4 Hz, 6.3 Hz), 4.07 (t, 2H,
5.3 Hz); HRMS ESI+ (m/z): 290.0706 [calculated for
C
13H8D7S3O (M + H+), 290.0722].
The reaction of 3a with formic acid in toluene. A dry toluene
solution (2mL) of 3a (3.0 mg, 0.015 mmol) containing 5 drops of
formic acid (95%) was heated to reflux. After 10 h, the reaction
mixture was allowed to cool to room temperature, 30 mL of a
saturated solution of NaHCO3 was added, and then the mixture
was extracted with CH2Cl2 (3 Â 5 mL). The combined organic
phase was dried over Na2SO4, separated and the solvent was then
1
removed under reduced pressure. H NMR spectroscopic analysis
identified the product to be 3b (30% conversion).
The reaction of 3a with p-TsOH in toluene.
A toluene
solution (2 mL) of 3a (5 mg, 0.026 mmol) and p-toluenesulfonic
acid monohydrate (0.2 g 1.05 mmol) was heated to reflux. After
3.5 h, the reaction mixture was allowed to cool to room
temperature, 30 mL of saturated aqueous NaHCO3 was added,
and then the mixture was extracted with CH2Cl2 (3 Â 5 mL).
The combined organic phase was dried over Na2SO4, the
organic solvent was removed, and the resulting brown gummy
material was purified by preparative TLC (silica, CH2Cl2) to
afford 4.1 mg (0.011 mmol, 45%) of 3-(2-thioxo-1,3-dithiol-4-yl)
propyl 4-methylbenzenesulfonate (12) as a pale yellow oil.
1
Characterization of 12. H NMR (CDCl3), d, ppm: 1.92–1.98
(m, 2H), 2.47 (s, 3H, Ar–CH3), 2.71 (td, 2H, 1.1 Hz, 7.4 Hz), 4.07
(t, 2H, 5.6Hz), 6.58 (s, 2H), 7.37 (d, 2H, 8Hz, Ar–H), 7.79
(d, 2H, 8 Hz, Ar–H); IR (neat), cmÀ1: 3101, 2958, 1728, 1356,
1180, 1066, 927; HRMS ESI+ (m/z): 346.9896 [calculated for
C13H15S4O3 (M + H+), 346.9904].
Synthesis of tetrahydro-3aH-[1,3] dithiolo[4,5-b]pyran-2-
one (5). A room temperature Schlenk flask was charged with
tetrahydro-3aH-[1,3]dithiolo[4,5-b]pyran-2-thione (3a) (0.10 g,
0.52 mmol), dry dichloromethane (10 mL), acetic acid (1 mL) and
mercuric acetate (0.20 g, 0.62 mmol). After 1 h, the color of the
reaction mixture changed from yellow to white with precipitation
of a white solid. After an additional 2 h, the solvent was removed,
the residue was then dissolved in chloroform, the organic solution
was filtered, and was then purified by passing through a silica
gel column to afford 88 mg (98%) of 5 as a white solid
(mp, 46–48 ꢀC). 1H NMR (C6H6), d, ppm: 0.72–0.78 (m, 1H),
0.85–0.96 (m, 1H), 1.06–1.16 (m, 1H), 1.18–1.25 (m, 1H),
2.79–2.88 (m, 1H), 3.26–3.28 (m, 1H), 3.42–3.48 (m, 1H), 4.66
(d, 1H, 10 Hz); 13C NMR (C6D6), d, ppm:189.36, 91.49, 69.73,
55.69, 26.90, 25.93; IR (KBr): 1653 (C═O); GC–MS (m/z): 177
(25%) (calculated for C6H9S2O2 (M + H), 177).
1
Characterization of 4. H NMR (C6D6), d, ppm: 1.31(q, 2H,
6.3 Hz), 2.02(td, 2H, 6.3 Hz, 1.6 Hz), 3.43(t, 2H, 5 Hz), 4.38(s,
2H), 6.94–7.01 (m, 3H, Ar–H), 7.06 (d, 2H, 8 Hz, Ar–H). 13C
NMR (CD3Cl): d, ppm: 227.42 (C═S), 154.9 (C═C), 135.21
(C═C), 129.5, 128.6, 128.01 (aromatic ring), 104.17 (aromatic
ring, bridging carbon), 66.18 (alcoholic carbon) 42.13 (methylene
carbon) 26.05. 22.92 (methylene carbon); IR (KBr): 1613 (C═C),
1093 (C═S); IR (neat), cmÀ1: 3391 (broad), 2912, 2847, 1799,
1609, 1156, 1050, 914; HRMS ESI+ (m/z): 283.0280 [calculated
for C13H15S3O (M + H+), 283.0282].
X-ray crystallography.
X-ray quality crystals were
obtained by slow evaporation of an acetonitrile solution of 3b.
Characterization of 3b. NMR data are tabulated in Table 2. IR
(C═S) 1078 cmÀ1; HRMS ESI+ (m/z): 192.9810 [calculated Àfo1r
Experimental data were collected at room temperature on a
Bruker SMART Apex II diffractometer using
a graphite
C6H9S3O (M + H+), 192.9810]; mp: 73–74 ꢀC. IR (neat), cm
:
monochromator and Mo-Ka (l = 0.071073 Å) radiation (0.8 mm
2937, 2913, 2847, 1425, 1301, 1033, 874, 502, 461.
collimator). Semi-empirical "Multi-Scan" absorption correction
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2013
Dithiolopyranthione Synthesis, Spectroscopy, and an Unusual Reactivity with DDQ
885
Table 4
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Crystal data for 3b.
Empirical formula
C6H8OS3
192.30
296(2)
Monoclinic
P21/c, 4
5.807(9)
12.99(2)
11.445(15)
113.23(6)
793(2)
Mr
Temperature (ꢀK)
Crystal system
Space group, Z
a, Å
b, Å
c, Å
ꢀ
b,
V, Å3
Crystal size, mm
0.7 Â 0.3 Â 0.1
r
calc, g cm–1
1.610
2θmax
51.58
8.58
0.0240
6563/1513
1.055
m(Mo–Ka), cmÀ1
Rint
Reflections collected/unique
GooF
R1/wR2 (I > 2s(I))
R1/wR2 (all data)
r
0.035/0.090
0.0485/0.0977
0.227/À0.177
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was performed using SADABS software [63]. Analysis of the
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structure being solved by the direct method implemented in
SHELXS and then refined by SHELXS program [64]. All non-
hydrogen atoms were located on a difference Fourier-map and
refined anisotropically. Hydrogen atoms were placed at
idealized positions (C–H distances were constrained at 0.98 Å)
and then refined using the Riding model approximation (U
(H) = 1.2Ueq(C)). The molecules of 3b in the crystal lattice were
found to be disordered through rotation around the S═C bond.
The disorder was successfully resolved by using SAME/DFIX
restraint of SHELXS and occupations of 0.58 and 0.42 for the
first and second disordered components, respectively. The C─C
bonds of the main disordered component were fixed to 1.54 Å
with a deviation of 0.02 Å. Final anisotropic parameters for C4b
were unreasonably low and O1b were unreasonably high
compared with the neighboring atoms. On the basis of the
thermal parameters and crystallization conditions, two different
conformations (enantiomers) are proposed. Oxygen atom O1b
of one enantiomer overlaps with carbon atom C4b of the other
enantiomer. Such positional disorder was resolved by
constraining coordinates and thermal displacement parameters to
be same for both positions. Occupations were fixed at 0.5. The
refined parameters are summarized in Table 4.
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Acknowledgments. We gratefully acknowledge the financial support
of the National Institutes of Health (GM 061555). Support
from the National Science Foundation DBI 0821401
(for mass spectrometry), CHE 0614785 (for NMR
spectrometer), and CHE 0234872 (for X-ray diffractometer)
are gratefully acknowledged.
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