CO2-promoted oxidative cross-coupling reaction for C-S bond formation via masked strategy in an odourless way

Article abstract of DOI:10.1039/c5cc03038b

Cu-catalyzed direct oxidative cross-coupling between boronic acids and masked sulfides delivering thioethers was described, in which the SO₃^-, as a mask, has shown a distinctive effect on the oxidative cross-coupling condition. Disulfide could be suppressed efficiently via masked strategy under CO₂ atmosphere. A broad scope of aromatics and scalable processes indicates its practicality, which could be further applied to drug late-stage modification and unsymmetrical dibenzothiophenes (DBTs) synthesis.

Full text of DOI:10.1039/c5cc03038b

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CO2-Promoted Oxidative Cross-Coupling Reaction for C-S Bond
Formation via Masked Strategy in an Odourless Way
Zongjun Qiao,a Nanyang Ge,a and Xuefeng Jiang*ab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
-
Cu-catalyzed direct oxidative cross-coupling between boronic that SO3 should be the right candidate for the mask because of its
acids and masked sulfides delivering thioethers was described, in unique properties: a) an electron withdrawing group preventing the
-
which the SO3 , as a mask, has shown a distinctive effect on strong coordination to metal; b) a sustained bulky group preventing
oxidative cross-coupling condition. Disulfide could be suppressed homo-coupling; and c) a conjugated group tuning the electron
efficiently via masked strategy under CO2 atmosphere. A broad effect on sulfur. In this manuscript, we will describe an odourless
scope of aromatics and scalable processes indicates its practicality, oxidative cross-coupling reaction through the concept of the
which could be further applied to drug late-stage modification and combination of mask-effect and enabling atmosphere (Scheme 1).
unsymmetrical dibenzothiophenes (DBTs) synthesis.
Transition-metal-catalyzed oxidative cross-coupling1 between
O
boronic acids and heteroatom nucleophiles has been well known as
the Chan−Lam reacꢀon2 and emerged as a powerful protocol for
the construction of carbon-nitrogen bonds3 or carbon-oxygen
bonds,4 due to a variety of readily available boronic acids and their
derivatives.5 However, direct cross-coupling between metallic
nucleophile and sulfide has been less studied,6 despite its
importance in the pharmaceutical industry,7 material science,8 and
food chemistry9 in the race toward organosulfur compounds
synthesis. There are three main reasons for this: a) strong
coordination of the lone pair electrons on sulfur to the transition
metal; b) preferential oxidization to disulfide when thiol meets
oxidant; and c) unpleasant smell during the experimental process.
Several couplings have been tried to construct carbon-sulfur bonds
through boronic acids mainly in virtue of stoichiometric metal,
special ligand, or by formation from disulfide or mercaptan with
Masked
H
R S
S ONa
R
S
O
I
Mask Eff ect
Electron Withdrawing Group
Sustained Bulky Group
Conjugated Groups
Prevent Strong Coordination
Prevent Homo-Coupling
Tune Electronic Ef fect
Figure 1. Masked sulfide
This work:
SO3Na
B(OH)2
S
Cu catalyst
oxidant
S
1
2
Ar2
Nu2
Ar1
+
mask-off
Nu1
Discovery of enabling atmosphere
♦
♦
: carbon dioxide
Broad Scope
: a range of aromatics, heteroaromatics,
unpleasant smell.10 Our group has focused on introducing
a
and natural products
♦ Application:
√ drug late-stage modification
√ unsymmetrical DBTs synthesis
designed mask to naked sulfur, which should possess certain
properties including electron effect, steric hindrance and resonance
stabilization (Fig. 1). Based on our odourless sulfur atom transfer
(SAT) findings11 and inspired by the first single crystal X-ray
diffraction analysis12 of the structure I (Bunte salts13), we envisioned
Scheme 1. Oxidative sulfurating cross-coupling reaction
We commenced our study with sodium S-p-tolyl sulfothioate 1a14
and phenylboronic acid 2a under standard conditions, (see ESI)
which afforded desired product 3a in 85% yield with less than 2% of
disulfide 4a under 80 oC (Fig. 2). However, when 4-
methylbenzenethiol served as a sulfur source, it tended to oxidize
to 4a in 49% yield. Both copper trifluoromethanesulfonate and
1,10-phenanthroline are necessary in this system, which indicated
the reaction is not capable of undergoing un-catalyzed nucleophilic
substitution. The consumption of trifluoromethanesulfonic acid was
a.Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department
of Chemistry, East China Normal University, 3663 North Zhongshan Road,
Shanghai, 200062, P. R. China.
b.State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, P. R.
China.
† Electronic Supplementary Information (ESI) available: Experimental procedures
and spectroscopic data for all new compounds. CCDC: 1034135 and 1034136. For
ESI and crystallographic data in CIF or other electronic format See
DOI: 10.1039/x0xx00000x
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B
addressed depending on different reactant. During the course of
condition optimization, the unique effect of carbon dioxide was
detected, which could give better conversion and yield compared to
inert gas (N2), reducing gas (CO, H2) or oxidizing gas (O2).
CO2
Figure 3. TGA curves for sodium S-3-methoxyphenyl sulfothioate (A) DSC-TG spectra of
CO2-bubbled organic thiosulfate salt (B) DSC-TG spectra of organic thiosulfate salt
bubbled by different gases.
Control experiments showed that the desired product 3a’ could be
obtained in a yield of 63% by CO2-bubbled thiosulfate salt (Table 1,
entry 1), which was similar to unbubbled salt under the CO2
condition (Table 1, entry 2). However, unbubbled thiosulfate salt
under a N2 atmosphere only achieved 37% yield, in which more
disulfide has been produced in the yield of 27% (Table 1, entry 3).
Alternatively, additives, which could generate CO2 in situ, were
subjected to the reaction under a N2 atmosphere, inhibiting
disulfide in different levels (Table 1, entries 4-6). These current
observations from the physical absorption phenomenon and
control experiments demonstrated that the enabling atmosphere
played the role of stabilization and slow oxidation of the revealed
thiolate to disulfide, perhaps by the formation of carbonate,
Figure 2. Dramatic atmosphere effect in oxidative sulfurating cross-coupling reaction
aSodium S-p-tolyl sulfothioate served as sulfur source. b4-methylbenzenethiol served as
sulfur source.
The interaction between organic thiosulfate salt and carbon dioxide
was preliminarily investigated. Carbon dioxide was bubbled into
sodium S-3-methoxyphenyl sulfothioate in methanol at ambient
temperature for 1 h, affording CO2-bubbled thiosulfate salt. There is
no sharp difference between bubbled and unbubbled organic
bicarbonate, or carbonic acid.
Table 1. Control Experiments
1
thiosulfate salt in the H NMR signal, which meant that a chemical
change has not taken place. Two kinds of thiosulfate salts were
investigated through 13C NMR spectroscopy as well, which showed
that one more peak (at about 126.3 ppm) was detected when using
CO2-bubbled (see ESI). Followed by thermogravimetric analysis
(TGA) in the temperature range of 30-800 oC under a flow of
nitrogen, the TG curve of CO2-bubbled thiosulfate salt displayed one
more stage, which showed a rapid initial weight loss of 2.0 wt %
before the release of water molecules in the temperature range of
90−100 oC (Fig. 3A). N2, O2, H2, or CO was bubbled into organic
thiosulfate salt, which has not shown similar stage (Fig. 3B). These
evidences implied that CO2 could partially prevent the formation of
disulfide in the form of physical absorption but not in a chemical
way.
The scope of this catalytic sulfuration was investigated in Table 2.
Generally, a variety of arylboronic acids, bearing both electron-
withdrawing and -donating groups at the para-, meta-, or ortho-
positions afford moderate to excellent yields (3a-3l). All halogen
substituted substrates proceed smoothly, such as F (3m), Cl (3n-3p),
Br (3q), and even I (3r), which was rarely benign in traditional cross-
coupling. On the other hand, diversity of organic thiosulfate salts
were also examined, which indicated that the electronic effect from
sulfur sources did not affect the efficiency of the transformations
either. The reaction was further extended to scalable processes, in
which sodium S-3-methoxyphenyl sulfothioate (1.2 g) could be
efficiently converted to 3a’ in 84% yield with even reduced loading
of catalyst (see ESI). Remarkably, the boronic acids embedded in
the tocopherol framework could provide thioether-substituted
2 | Chem. Commun., 2015, 00, 1-3
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Table 2. Substrate Scopea, b
aReaction conditions: 1 (0.1 mmol), 2 (0.15 mmol), Cu(OTf)2 (20 mol%), 1, 10-phen (40 mol%), Ag2CO3 (0.12 mmol), K3PO4 (0.14 mmol), DTBP (0.1 mmol), and DMF (2.0 mL); 80 oC; 7
h. bIsolated yields. c0.03 mmol of CF3SO3H was added. d0.05 mmol of CF3SO3H was added.
Table 3. Sulfuration of Heteroarenes.a, b
Table 4. Application in Parmaceutical and Material
aReaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), Cu(OTf)2 (20 mol%), 1, 10-phen (40
mol%), Ag2CO3 (0.12 mmol), K3PO4 (0.14 mmol), DTBP (0.1 mmol), and DMF (2.0 mL);
80 oC; 7 h. bIsolated yield. cCu(OTf)2 (20 mol%) was replaced by CuCl2. dCu(OTf)2 (0.1
mmol), 1, 10-phen (0.1 mmol).
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tocopherol 3b’ in 73% yield, which has shown potential value in
complex molecule modification.
Heteroaromatics are always crucial and challenge in drug
discovery,15 whose coupling was also demonstrated in Table 3.
Compounds containing nitrogen (5a, 5b, and 5c), oxygen (5d), and
sulfur (5e and 5f) atoms all performed well. Ferrocene-containing
product 5g16 could be achieved in moderate yield, which provides
the opportunity for developing new sulfur-containing ferrocene
ligands.
This method could be readily applied to drug late-stage
diversification (Table 4A).17 Estratrien, a kind of female hormone
drug, could be easily transformed to the corresponding organic
thiosulfate salt in 94% yield, to afford sulfur-modified estratrien 6a
followed by oxidative sulfurating cross-coupling. Sulfur-decorated
Fenofibrat 6b could derive from its boronic acid ester efficiently
through a similar transformation. This method offers great potential
for the generation of drug analogue libraries. From another aspect,
this method could be carried out to establish unsymmetrical
dibenzothiophenes (DBTs), which consititute a core framework in
certain kinds of organic compounds including pharmaceuticals,
photoactive compounds, dyes, liquid crystals, and conducting
polymers (Table 4B).8,18 For example, benzo[d]naphtho[1,2-
b]thiophene which was substituted by OMe, F, or Cl could be
obtained untrammeled through this protocol followed by oxidative
dehydrogenative cyclization.19
8
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-
In conclusion, relying on the versatile effect of SO3 and CO2, sulfur
could be compatible with oxidizing condition in an odourless way. A
dramatic masked strategy and an interesting CO2 accelerated
phenomenon were uncovered, which have been studied by TGA.
The extensive adaptability of this sulfuration present in both
reactants renders this reaction highly efficient and practical for the
synthesis of medicinally important and materially unobtainable
units using readily available boronic acids. Further explorations for
more synthetic applications are ongoing in our laboratory.
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under N2 atmosphere, the salts could be obtained by
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Financial support was provided by NBRPC (973 Program,
2015CB856600), NSFC (21472050, 21272075), NCET (120178),
DFMEC (20130076110023), Fok Ying Tung Education Foundation
(141011), the program for Shanghai Rising Star (15QA1401800),
Professor of Special Appointment (Eastern Scholar) at Shanghai
Institutions of Higher Learning, and the Changjiang Scholar and
Innovative Research Team in University.
16 CCDC-1034135 (5g): See the ESI† for details.
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