Super electron donor-mediated reductive desulfurization reactions

Article abstract of DOI:10.1039/c9cc06775b

The desulfurization of thioacetals and thioethers by a pyridine-derived electron donor is described. This methodology provides efficient access to the reduced products in high yields and does not require the use of transition-metals, elemental alkali-metals, or hydrogen atom donors.

Full text of DOI:10.1039/c9cc06775b

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Super electron donor-mediated reductive
desulfurization reactions†
Cite this: Chem. Commun., 2019,
55, 12968
Kanako Nozawa-Kumada, * Shungo Ito, Koto Noguchi, Masanori Shigeno
Yoshinori Kondo*
and
Received 31st August 2019,
Accepted 7th October 2019
DOI: 10.1039/c9cc06775b
rsc.li/chemcomm
The desulfurization of thioacetals and thioethers by a pyridine- approach by the reductive desulfurization of thioacetals using
derived electron donor is described. This methodology provides photoinduced electron transfer from t-BuOK in the presence of
efficient access to the reduced products in high yields and does not the hydrogen atom donor 1,4-cyclohexadiene.5 Furthermore,
require the use of transition-metals, elemental alkali-metals, or Provot et al. developed a desulfurization methodology using the
hydrogen atom donors.
TMSCl/NaI system.6 While these methods allow desulfuriza-
tion, they require a hydrogen atom donor as an additive or the
Compounds comprising carbon–sulfur bonds are important in use of large excess of reagents. Further, their substrate scope
organic chemistry due to the varied roles they play, such as is limited to thioacetals. In 2015, Akiyama et al. reported
stabilizing the carbanions generated adjacent to the C–S bond,1 the desulfurization of thioacetals and thioethers using the
behaving as an electrophile in coupling reactions,2 and behaving B(C6F5)3–Et3SiH system.7
as a directing group for transition-metal-coupling reactions.3
We recently reported the development of super-electron-donor
Particularly, in compounds such as dithioacetals, the stabilization (SED)-mediated reduction of organic compounds.8 Organic SEDs
of the carbanions generated adjacent to the C–S bonds allows were first reported by Murphy’s group and displayed superior
functionalization by reaction with electrophiles, for C–C bond reduction potential than well-known organic electron donors,
formation. The subsequent desulfurization delivers the new C–C such as tetrathiafulvalene (TTF) or 1,1,2,2-tetrakis(dimethyl-
bond in the absence of the sulfur moiety, due to which, compounds amino)ethylene (TDAE) (Fig. 1).9 Many transition-metal and
containing C–S bonds can be treated as carbanion equivalents, alkali-metal free reductions have been developed using SEDs.
and are therefore considered as useful building blocks in For example, reductions of sulfonamides/sulfones,9c Weinreb-
organic chemistry. As illustrated by this example, desulfuriza- amides,9f acyloin derivatives,9g triflate esters/triflamides,9i
tion of the C–S bond to the C–H bond is an important chemical malononitriles9m and nitrobenzenes8,9q have been reported using
transformation.4 RANEYs nickel-catalyzed reduction of the C–S SEDs. Continuing our interest on the applications of SEDs for
bond is one of the most widely used methods for this transfor- novel transformations, we report here, a novel desulfurization of
mation. Reactions using other nickel species or elemental thioacetals and thioethers mediated by a pyridine-derived SED
alkali-metals have also been reported for this transformation. which does not require the use of transition-metals, alkali metals,
However, these methods use reagents that are difficult to or hydrogen atom donors as additives. This reaction can be
handle and/or require prior preparation before use. In addition successfully applied to various thioacetals and thioethers bearing
to these methods, desulfurization mediated by greater than methyl, methoxy, halogen (fluoride, chloride, and bromide),
stoichiometric amounts of other transition-metals (Zn, Cu, cyano, keto, and amide group substitutions on the benzene rings.
Mo etc.) has been developed.4b In this context, the development
of a transition- or alkali-metal-free transformation method for
desulfurization is required for realizing an economical and
˜´˜
green process. For example, Penenory et al. reported one such
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki,
Aoba-ku, Sendai 980-8578, Japan. E-mail: kumada@m.tohoku.ac.jp,
ykondo@m.tohoku.ac.jp
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9cc06775b
Fig. 1 Organic electron donors.
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Table 1 Effect of reaction parameters
Table 2 Desulfurization of 2,2-diaryl-1,3-dithianes and 2-acyl-2-aryl-1,3-
dithianes 1
Entry
Variation from standard conditions
Yielda (%)
1
2
3
4c
5
6
7
None
93 (85)b
8
11
N.R.
81–91
83
4 (from 40) instead of 3
5 (from 50) instead of 3
Without 3
DMA, DMSO, or DMPU instead of DMF
At 80 1C
KHMDS or K2CO3 instead of NaH
37–81
a
N.R.
=
no reaction.
Determined by 1H-NMR using 1,1,2-
b
trichloroethane as an internal standard. Isolated yield is given in
c
parentheses. Without 30 nor NaH.
We began the optimization of the desulfurization reaction
using 2,2-diphenyl-1,3-dithiane 1a as the test substrate (Table 1).
The various electron donors shown in Table 1 were used in the
optimization screen. The procedure involved the initial in situ
generation of the SED by mixing 1.5 equiv. of its precursor with
3.0 equiv. of NaH in DMF at room temperature for 1 h. The
Isolated yields. Yields in parentheses were determined by 1H-NMR analysis.
a
c
b
Reaction temperature was 60 1C. Reaction temperature was 120 1C.
d
Reaction temperature was 80 1C. 15% of 4-bromodiphenylmethane
e
was determined by 1H-NMR. Reaction temperature was 140 1C.
dithiane 1a was then added to the generated SED in a glove box, reaction conditions and afforded the corresponding products
and the resulting mixture was stirred at 100 1C for 24 h. We first in good to high yields (2g–2i). Dithianes carrying electron-
studied the use of the pyridine-derived SED 3 (SED-2 in Fig. 1) for withdrawing groups such as an ester or a nitrile group on the
the desulfurization reaction and obtained the desired product 2a benzene rings reacted to provide the diarylmethanes 2j and 2k
in high yield (entry 1). The use of organic electron donors 4 in good yields. On the other hands, the use of the substrate 1l
and 5,10 which displayed lower reduction potential compared bearing a nitro group did not proceed to form any desired
to 3, led to a drastic decrease in the yield of 2a (entries 2 and 3). product. Substrates carrying two halogen substituents or two
The reactions carried out in the absence of 3 did not afford any methyl groups on both rings also proceeded to deliver the
product (entry 4). Further, we carried out a solvent screening desired products in good yields (2m–2p). However, methoxy
with a variety of solvents, such as DMA, DMSO, and DMPU, or dimethylamino substituents on the p-position of either rings
which were found effective for the reaction (entry 5). Decreasing led to a marked decrease in the product yields (2q and 2r). The
the reaction temperature to 80 1C led to a slightly lower yield reaction with the substrate carrying methyl substitutions on the
(entry 6). The use of KHMDS or K2CO3 instead of NaH for the o- and p-positions of either rings afforded the desired product
in situ generation of 3 decreased the yield (entry 7).
in good yield, indicating that this reaction was not affected by
With the optimized conditions in hand, we explored the scope steric hindrance (2s). Furthermore, this method could be applied to
of viable substrates for the desulfurization reaction using a series acyl substituted 1,3-dithianes 1t and 1u and gave the desulfurized
of 2,2-diaryl-1,3-dithianes 1 (Table 2). First, substrates bearing a products in moderate yields (2t and 2u).
methyl group on one of the benzene rings were tested and formed
In addition to the substituted 2,2-diaryl-1,3-dithianes, the
the desulfurization product in high yields regardless of the reaction conditions were also applied to 2,2-diphenyl-1,3-dithiolane
position of the methyl substitution on the ring (2b–2d). The 6a, which afforded the corresponding product 2a in moderate
use of a higher temperature (120 1C) was effective for reactions yield (Scheme 1).
with substrates carrying the methoxy or dimethylamino group
Having obtained good yields with bis aryl substrates, we attempted
(2e and 2f). Substrates containing halogen atoms such as to study the substrate scope of 2-alkyl-2-aryl-1,3-dithianes. However,
fluorine, chlorine, and bromine were well tolerated under the the reaction of 2-benzyl-2-phenyl-1,3-dithiane 7a did not work
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Table 4 Desulfurization of thioethers 9
Scheme 1 Desulfurization of 2,2-diphenyl-1,3-dithiolane 6a.
Entry Substrate
Product
Conditions Yield (%)
under the conditions optimized for 2,2-diphenyl-1,3-dithiane 1a.
Murphy et al. reported the increased reduction ability of 3 under
UV (352 nm) photolysis and showed that the dehalogenation of a
chlorobenzene derivative proceeded cleanly upon using the
photoactivated electron donor 3.9j Therefore, we investigated
the use of this photoactivated electron donor 3 and found that
it is effective for C–S bond cleavage of 7a and furnished the ring-
opened thiol product (8a) in moderate yield. Substrates bearing
other alkyl groups such as methyl, butyl, and tertiary butyl also
gave the corresponding thiols in moderate yields (8b–8d).
Furthermore, the reduction of 2-monosubstituted-1,3-dithiane
7e proceeded to give 8e in 43% yield (Table 3).
We next examined the use of the developed reaction condi-
tions for the desulfurization of thioethers (Table 4). First, when
aryl diarylmethyl sulfides 9aa and 9ab were investigated under
the conditions optimized for 1a (Table 1, entry 1), the desired
product 10a was obtained in high yields (entries 1 and 2). After
a detailed optimization of the reaction conditions using iso-
propyl group substituted benzyl sulfide 9b, we found DMSO to
be most effective for the reaction, which afforded the desired
product 10b in good yield (entry 3).11 Furthermore, the reaction
of ethyl group substituted benzyl sulfide 9c also proceeded in
DMSO as a solvent (entry 4). The reaction of the alkyl sulfides
9da–9dc proceeded under UV (352 nm) photolysis to furnish
the desired product 2a (entries 5–7).12
1
A
A
B
95
94
70
2
3
4
B
43
5
6
C
C
65
95
Having studied the scope of the reaction, we conducted
control experiments to investigate the mechanism (Scheme 2).
When the reaction of the thiol 11, which is the product obtained
by a single C–S bond cleavage of 1a, was conducted under the
optimized desulfurization conditions, 2a was obtained in a high
yield (Scheme 2a) indicating that 11 is an intermediate during
the desulfurization process, which occurs in a step-wise fashion.
We next studied the reaction of 11 in the presence of three
different bases to investigate if the second C–S bond cleavage
7a
C
93
Condition A: 3 (1.5 equiv.) in DMF at 100 1C for 24 h, Condition B: 3
(3.0 equiv.) in DMSO at 140 1C for 24 h, Condition C: 3 (3.0 equiv.)
in DMF under UV (352 nm) photolysis at room temperature for 72 h.
a
3 (4.5 equiv.) was used.
Table 3 Desulfurization of 2-alkyl-2-aryl-1,3-dithianes and 2-phenyl-1,3-
dithiane 7
Scheme 2 Control experiments.
was mediated by electron transfer from 3. The desulfurization
occurred in the presence of the three bases, NaH, NaOH and
DBU, suggesting that the cleavage of the second C–S bond would
not proceed by electron acceptance from 3 (Scheme 2b).
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Fig. 2 Proposed mechanism for desulfurization of 1a.
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On the basis of these experimental studies, a plausible
mechanism for the desulfurization reaction of dithiane 1a is
proposed (Fig. 2). The first step involves a two-electron transfer
from 3, leading to the C–S bond cleavage of 1a affording the
dianion species 12. Subsequent protonation of 1213 is followed
by the second C–S bond cleavage by an intramolecular attack of the
sulfur anion at another sulfur atom,14 leading to the formation of
the diphenyl methilide 14 which undergoes protonation to afford
the desired product 2a. The stability of the resulting anionic species
largely affects the second step of the reaction. Diphenyl methilide is
a stable anionic species, while phenylalkyl methilide is not very
stable, due to which the second step of C–S bond cleavage does not
proceed efficiently.
In summary, a novel SED (3)-mediated reductive desulfurization
of thioacetals and thioethers that obviates the need for the use
of transition-metals or alkali-metals is reported. The developed
reaction conditions display a broad substrate scope and include
methyl, methoxy, halo (fluoride, chloride, and bromide), cyano,
keto, and amide group substitutions on the aryl ring. Further
studies to expand the substrate scope and exploration of other
applications of the methodology to develop novel molecular trans-
formations under metal-free conditions are under investigation.
This work was financially supported by the Japan Society for
the Promotion of Science (JSPS) KAKENHI Grant no. 19H03346
and 19K16309. This work was also supported by Grand for Basic
Science Research Projects from The Sumitomo Foundation and
the Platform Project for Supporting Drug Discovery and Life
Science Research funded by Japan Agency for Medical Research
and Development (AMED).
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Conflicts of interest
There are no conflicts to declare.
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