Reduction of CO2 into Methylene Coupled with the Formation of C-S Bonds under NaBH4/I2 System

Article abstract of DOI:10.1021/acs.orglett.8b02730

A selective four-electron reduction of CO₂ with thiophenol using NaBH₄ as a reductant is described to access dithioacetals. This reaction provides a novel synthetic method for the highly selective conversion of CO₂ into methylene, and a new access to molecular structures via formation of C-S bonds using CO₂ as the C1 source.

Full text of DOI:10.1021/acs.orglett.8b02730

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Reduction of CO2 into Methylene Coupled with the Formation of
C−S Bonds under NaBH4/I2 System
Zhiqiang Guo,†,‡,§ Bo Zhang,‡,§ Xuehong Wei,† and Chanjuan Xi*,‡
†Scientific Instrument Center, Shanxi University, Taiyuan 030006, China
‡MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University,
Beijing 100084, China
S
* Supporting Information
ABSTRACT: A selective four-electron reduction of CO2 with thiophenol using
NaBH4 as a reductant is described to access dithioacetals. This reaction provides a
novel synthetic method for the highly selective conversion of CO2 into methylene,
and a new access to molecular structures via formation of C−S bonds using CO2 as
the C1 source.
Scheme 1. Reactions To Proceed Dithioacetals
arbon dioxide (CO2) has shown great potential as an
Cimportant and ideal one-carbon (C1) source in chemical
feed-stock due to its nontoxicity, abundance, availability, and
recyclability.1 Although great progress in activation and
incorporation of CO2 into valuable chemicals has been
achieved, most methods for constructing C−C, C−O, and
C−N bonds are based on a two- or six-electron CO2 reduction
through molecular catalysis due to its kinetic and thermody-
namic stability.2 The four-electron reduction of CO2 is rarely
applied in organic synthesis. In this regard, Cantat et al. first
reported the TBD-catalyzed four-electron reduction of CO2
coupld with secondary aromatic amines to access aminals.3
Bontemps immediately reported the iron-catalyzed selective
reduction of CO2 to bis(boryl)acetal, which is used as a
reactive and versatile methylene transfer agent to construct
new C−N, C−O, C−C, CN, and CC bonds in a one-pot
two-step procedure.4 He and Han described the glyscine
bestaine as an efficient and renewable catalyst for hierarchical
two-, four-, and six-electron reduction, respectively.5 Recently,
Klankermayer′s group reported a Ru- and Co-based cocatalyst
for the synthesis of dimethoxymethane with CO2 as a
methylene source.6 In addition, Xia’s group has reported a
TBD-catalyzed reductive tandem C−C and C−N bond-
forming reaction with CO2 as a methylene source to generate
spiroindolepyrrolidines.7 However, the challenging four-elec-
tron reduction of CO2 in combination with the formation of
the C−S bond simultaneously remains unresolved.
Of all the sulfur compounds, dithioacetals are widely applied
in organic synthesis and organic coordination chemistry as well
as the biological, pharmaceutical, and pesticidal fields.8 Various
reactions’ access to dithioacetals have been disclosed, and they
could be summarized in two methods: the first one is insertion
of methylene into disulfide bonds using diazomethane, sulfur
ylides, and lithium or zinc carbenoids as the methylene source
(Scheme 1a).9 Very recently, Chen reported an efficient
halogen-free Cs2CO3-promoted methylene insertion into
disulfide bond access to dithioacetals using acetone as a
methylene source.10 The second one is the condensation of
thiols with activated methylene halides or aldehydes (Scheme
1b).8d,e,11 Even so, there are still some drawbacks such as high
temperatures, a noble metal catalyst, and an excess amount of
base or stronger reductants. Therefore, development of a new
reaction for the preparation of important dithioacetals is still
desirable.
Herein, we report the first selective four-electron reduction
of CO2 with thiophenol using mild NaBH4 as a reductant to
generate dithioacetals (Scheme 1c). This reaction realized
selective conversion of CO2 into methylene in combination
with the formation of two C−S bonds simultaneously.
Moreover, our method is green, scalable, and with a broad
substrate scope as well as good functional group tolerance.
Continuing our interest in the development of reductive
functionalization of CO2,12 we hypothesized that mild NaBH4
could realize reduction of CO2 coupled to C−S bond
construction. The initial optimization studies were explored
using p-thiocresol 1a (0.5 mmol) as a model substrate to test
our hypothesis. The results are listed in Table 1. The reaction
could hardly proceed without any additive or catalyst (Table 1,
Received: August 25, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02730
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
representative results are summarized in Scheme 2. The para-
substituted thiocresols with electron-donating groups exhibited
Table 1. Optimization of Reaction of CO2 with
Thiophenol
a
Scheme 2. Substrate Scope for Reductive Functionalization
a b
,
of CO2
b
entry NaBH4 (equiv)
additive
solvent
yield (%)
1
2
3
4
5
6
7
8
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
2.5
2
−
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
acetonitrile
DMF
DMSO
THF
toluene
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
−
I2 (0.2 equiv)
I2 (0.5 equiv)
I2 (0.7 equiv)
I2 (1.0 equiv)
NIS (1.0 equiv)
NaI (1.0 equiv)
TBAI (1.0 equiv)
I2 (1.0 equiv)
I2 (1.0 equiv)
I2 (1.0 equiv)
I2 (1.0 equiv)
I2 (1.0 equiv)
I2 (1.0 equiv)
I2 (1.0 equiv)
I2 (1.0 equiv)
I2 (1.0 equiv)
19
84
94
99 (92)
21
−
−
6
−
−
19
5
90
79
95
88
9
10
11
12
13
14
15
16
17
c
d
a
Reaction conditions: p-thiocresol (62.1 mg, 0.5 mmol), NaBH4, 1
atm of CO2, 1,4-dioxane (1.0 mL), I2 (0.5 mmol), 100 °C, 24 h.
b
Yield determined by 1H NMR using trichloroethylene as an internal
c
d
standard; isolated yield is given in parentheses. 20 h. 90 °C.
entry 1). In view of the NaBH4/I2 reagent combination, they
are easier to handle and relatively more stable toward
atmospheric air and moisture compared to other hydride
reducing agents,13 and employing the NaBH4/I2 system should
be useful in large scale applications. Therefore, the reaction
was treated in 1,4-dioxane solution at atmospheric pressure of
CO2 using 3 equiv of NaBH4 as a reductant and I2 (20 mol %)
as an additive at 100 °C within 24 h. To our delight, the
selective four-electron reduction product, bis(p-tolylthio)-
methane 2a, was obtained in 19% yield (entry 2). When
increasing the amount of I2, the yield of 2a increased obviously
(entries 2−5), Notably, the reaction of 1a with 1 equiv of I2
afforded the desired product 2a in nearly quantitative yield
(99%, entry 5). Then several representative iodic compounds
such as N-iodosuccinimide (NIS), sodium iodide (NaI), and
tetrabutylammonium iodide (TBAI) were screened (entries
6−8). The reductive product 2a could be obtained in 21%
yield when using NIS as an additive, indicating that the iodine
cation plays a key role in this process. Then, different solvents
such as tetrahydrofuran (THF), acetonitrile, dimethyl
formamide (DMF), dimethyl sulfoxide (DMSO), and toluene
were screened (entries 9−13), and poor yields were observed,
which indicated that the solvent also plays a critical role on the
selectivity and reactivity of the reaction. Furthermore,
shortening the reaction time to 20 h gave a 90% yield of 2a
(entry 14). In addition, the reaction temperature was also
examined and the yield of 2a reduced to 79% (entry 15). The
best temperature for obtaining a satisfactory yield was 100 °C.
When we decreased the amount of NaBH4 to 2 equiv, the yield
of 2a was reduced to 88% (entry 17). When the NaBH4 and I2
reductive system was replaced by BH3·THF, the dithioacetal
2a was not detected.
a
Reaction conditions: Thiocresols (0.5 mmol), NaBH4 (1.5 mmol),
CO2 1 atm, 1,4-dioxane (1.0 mL), iodine (0.5 mmol), 100 °C, 24 h.
b
Yield determined by 1H NMR using trichloroethylene as an internal
standard; isolated yields were given in parentheses.
higher reactivity, and the corresponding dithioacetals were
obtained in over 95% yields (2a−2d and 2h). Comparatively,
the para-substituted thiocresols with electron-withdrawing
groups are relatively inert, only giving the desired products
in moderate yields because of weak nucleophilicity (2i−2k and
2n). A substrate bearing a strong electron-withdrawing group
such as 4-nitro-benzenethiol failed to give the corresponding
product 2o. In addition, substituent groups such as −CH3 and
−Cl at the meta or ortho position of the aromatic ring, as well
as naphthyl, were well tolerated. The desired bis(arylthio)-
methanes 2e−2f, 2l−2m, and 2p were isolated in moderate to
excellent yields (71−94%), indicating that the electronic effects
were not evident in this process. And to our delight, the crystal
of 2p was suitable for single-crystal analysis; its structure was
further confirmed by X-ray diffraction analysis. The substrate
bearing methyl groups at both ortho positions also gave a 65%
yield of the corresponding product 2g due to the steric
hindrance of ortho substituents. Notably, the reductive
cyclization of o-phenyldithiol with CO2 could proceed
successfully under the current conditions to afford the
With the optimized reaction conditions in hand, the scope of
this protocol with various thiocresols was investigated. The
B
DOI: 10.1021/acs.orglett.8b02730
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Letter
corresponding 1,3-benzodithiole 2q and 2r in 70% and 71%
yield, respectively. When the 2-hydroxy-thiophenol 1s was
used as the substrate, the 2,2′-(methylenedithio)diphenol 2s
was obtained in 67% yield. Additionally, this protocol applied
to heteroarotic thiophenols, such as 2-pyridinylthiol and
thiophene-2-thiol, to afford the corresponding products in
low yields (2t in 13% NMR yield, 2u in 37% yield,
respectively). We also chose some representative aliphatic
thiophenols for screening, and the expected reactions smoothly
occurred with moderate yields of the products (2v−2y). It is
noteworthy that 1,3-dithiane (2z), a useful synthetic
intermediate with widely applications in organic and medicinal
chemistry, can be gained in 67% yield through the reductive
functionalization of CO2 with 1,3-propanedithiol.
mixture was heated to 80 °C for 0.5 h, iodine was then added
and the reaction mixture was heated to 100 °C for 24 h to
afford dithioacetal 2a in nearly quantitative yield (eq 5).
Furthermore, the reaction mixtures of CO2, NaBH4, 1a, and I2
were monitored in situ by NMR in 1,4-dioxane-d8 at 100 °C for
0.5, 1, and 3 h, respectively (for NMR spectrum, see the
1
Supporting Information of Figure S2−S5). In the H and 13C
NMR spectra, signals around 4.90 and 78.4 ppm were
obtained, which were assigned to the B−O−CH2SPh moiety,
and the results are consistent with the reported literature.14 To
further confirm the methylene unit in the dithioacetal, 13CO2
was used in the reaction and an expected product was
obtained. It indicates the methylene unit comes from carbon
dioxide (for NMR spectrum, see Supporting Information
Figure S6). The reaction of diphenyl disulfide 3 with NaBH4
and CO2 under the optimized conditions afforded thiophenol
4 (eq 6). Furthermore, diphenyl disulfide 3 with NaBH4 and
CO2 at 80 °C for 0.5 h, followed by the addition of I2 under
the optimized conditions, afforded dithioacetal in 71% NMR
yield (eq 7). These results indicate that diphenyl disulfide 3 is
not the intermediate.
In order to verify the applicability of the current method-
ology, the reaction was amplified to 10 mmol scale with a yield
of bis(p-tolylthio)methane in 80% (1.04 g) under the standard
conditions in 20 mL of 1,4-dioxane (eq 1).
Based on the above experimental results on the reductive
functionalization of CO2 and NaBH4 with thiol in the presence
of iodine, a possible pathway is elucidated as shown in Scheme
4. First, NaBH4 reacts with thiol 1 to give hydrogen and
The net result of this reductive functionalization of CO2 is
the cleavage of two CO bonds and the formation of two C−
H bonds and two C−S bonds, which is rare to form
dithioacetals via the complete deoxygenation of CO2. In
order to clarify the reaction process, controlled experiments
were conducted (Scheme 3). The reaction cannot proceed in
Scheme 4. Possible Mechanism of CO2 and NaBH4 with
Thiophenol in the Presence of Iodine
Scheme 3. Controlled Experiments
compound A that may also inhibit the subsequent oxidation of
thiol 1 by I2. On the other hand, molecular NaBH4 reacts with
I2 to release borane and hydrogen. The borane reacts with
carbon dioxide to produce B (peaks at 7.92−8.10 ppm
observed apparently in situ after addition of iodine).15 The
intermediate A undergoes formylation with B to generate a
compound C and boroxane. The compound C reacts with BH3
to generate intermediate D, which reacts with A to release
dithioacetal 2 and boroxane.
In summary, we have described a novel reaction including
selective four-electron reduction of CO2 with thiophenols to
access dithioacetals using the NaBH4/I2 system. This reaction
is the first selective four-electron reductive functionalization of
CO2 coupled with the construction of C−S bonds. In this
system, a variety of thiophenols could be turned into the
desired dithioacetals in moderate to excellent yields. The
reaction could also be applied at gram scale. Further detailed
studies on this selective reductive mechanism and to expand
the utility of this system are in progress in this group.
the absence of iodine, and Me-PhSH was recovered after
hydrolysis (eq 2). When NaBH4, thiophenol, iodine, and CO2
were added together at the beginning of the reaction,
dithioacetal 2a is only obtained in 8% yield after 24 h at 100
°C, the major product is disulfide (eq 3). NaBH4, iodine, and
CO2 were added together at the beginning of the reaction and
heated to 80 °C. After 0.5 h, 4-toluenethiol 1a was then added
and heated to 100 °C for 24 h to afford trace dithioacetal 2a
accompained with formation of an amount of disulfide, which
indicates I2 directly oxidized thiophenol when they were added
together (eq 4). While the NaBH4, 4-toluenethiol 1a, and CO2
were added together at the beginning of the reaction and the
C
DOI: 10.1021/acs.orglett.8b02730
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Zhou, B.; Wu, C.; Han, B. ACS Sustainable Chem. Eng. 2017, 5, 7086−
7092.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02730.
■
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Accession Codes
CCDC 1859049 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: cjxi@tsinghua.edu.cn.
ORCID
(10) Chen, Q.; Yu, G.; Wang, X.; Huang, Y.; Yan, Y.; Huo, Y. Org.
Biomol. Chem. 2018, 16, 4086−4089.
(11) (a) Xia, J.; Yao, R.; Cai, M. Appl. Organomet. Chem. 2015, 29,
221−225. (b) Zaidi, J. H.; Naeem, F.; Khan, K. M.; Iqbal, R.; Zia-
Ullah. Synth. Commun. 2004, 34, 2641−2653.
Zhiqiang Guo: 0000-0001-5444-7455
Xuehong Wei: 0000-0002-9490-7265
Chanjuan Xi: 0000-0002-9602-7309
Author Contributions
§Z.G. and B.Z. contributed equally.
(12) Guo, Z.; Zhang, B.; Wei, X.; Xi, C. ChemSusChem 2018, 11,
2296−2299.
(13) Periasamy, M. ACS Symp. Ser. 2001, 783, 65−78.
(14) Barsamian, A. L.; Blakemore, P. R. Organometallics 2012, 31,
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Notes
(15) (a) Zhang, B.; Du, G.; Hang, W.; Wang, S.; Xi, C. Eur. J. Org.
Chem. 2018, 2018, 1739−1743. (b) Fujiwara, K.; Yasuda, S.; Mizuta,
T. Organometallics 2014, 33, 6692−6695.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the National
Natural Science Foundation of China (Nos. 91645120,
21472106, and 21871163).
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