Novel Bifunctionalization of Activated Methylene: Base-Promoted Trifluoromethylthiolation of β-Diketones with Trifluoromethanesulfinyl Chloride

Article abstract of DOI:10.1002/chem.201901781

A novel bifunctionalization of activated methylene was achieved successfully through the base-promoted trifluoromethylthiolation of β-diketones or β-ketoesters with trifluoromethanesulfinyl chloride. A series of α-trifluoromethylthiolated α-chloro-β-diketones and α-chloro-β-ketoesters were obtained in moderate to good yields under mild conditions. When β-diketones containing a phenyl group with a hydroxyl or amino substituent at the ortho position were used as substrates, intramolecular trifluoromethylthiolation/cyclization reaction took place to give the corresponding cyclic products. Furthermore, the protocol could be extended to perfluoroalkylthiolation with the sodium perfluoroalkanesulfinate/POCl₃ system. On the basis of experimental results, plausible mechanisms are proposed.

Full text of DOI:10.1002/chem.201901781

A Journal of
Accepted Article
Title: Novel Bifunctionalization of Activated Methylene: Base-
Promoted Trifluoromethylthiolation of ꢀ-Diketones with
Trifluoromethanesulfinyl Chloride
Authors: Jin-Tao Liu, Dong-Wei Sun, and Min Jiang
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To be cited as: Chem. Eur. J. 10.1002/chem.201901781
Link to VoR: http://dx.doi.org/10.1002/chem.201901781
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COMMUNICA
DOI: 10.1002/chem.200((will be filled in by the editorial staff))
Novel Bifunctionalization of Activated Methylene: Base-Promoted
Trifluoromethylthiolation of -Diketones with Trifluoromethanesulfinyl
Chloride
Dong-Wei Sun, Min Jiang,* and Jin-Tao Liu*[a]
Dedication ((optional))
The introduction of fluorine-containing group into organic
compounds may profoundly change their properties.[1] Among
various fluorine-containing groups, trifluoromethylthio (CF3S)
plays an important role in organofluorine chemistry owing to its
unique features such as remarkable electron-withdrawing effect,
excellent lipophilicity and metabolic stability.[2] In addition, the
enhancement of biological activity has also been found in some
trifluoromethylthio-containing compounds such as Tiflorex,
Cefazaflur and Toltrazuril.[3] Accordingly, the development of
efficient methods for assembling the SCF3 moiety into organic
molecules[4] for drug development is of great importance.[5]
the preparation of the trifluoromethylthiolating reagent requires
several steps and expensive reagents.
Trifluoromethanesulfonyl
chloride
(CF3SO2Cl),
trifluoromethanesulfinyl chloride (CF3SOCl) and sodium
trifluoromethanesulfinate (Langlois reagent, CF3SO2Na) are
cheap and easily available commercial chemicals.[11] Since
Zhang’s group reported firstly the use of sodium
trifluoromethanesulfinate
in
copper-catalyzed
trifluoromethylthiolation reaction of indoles,[12] transition metal-
free electrophilic trifluoromethylthiolation reactions with
CF3SO2Na/[P] or CF3SO2Cl/[P] reagent system have been
successively developed by Cai’s, Lu’s and our group.[13] Recently,
we reported an efficient trifluoromethylthiolation-based vicinal
bifunctionalization of indoles using CF3SO2Na/POX3 system, in
which a halogen atom was introduced into the 2-position at the
same time under mild conditions,[14] and Zhang et al. reported the
trifluoromethylthiolation of ketones with CF3SOCl (Scheme 1, eq.
2).[15] In our continuous study on the development of
On the other hand, carbonyl compounds constitute a large
family of interesting building blocks for organic synthesis, and a
wide range of bioactive and natural compounds possess a
carbonyl
function.[6]
Consequently,
introducing
the
trifluoromethylthio group into carbonyl compounds could be of
great value for further applications, and the α-functionalization of
a carbonyl group appears to be a privileged and efficient approach
to construct the C–SCF3 bond. Since the pioneering work on the
trifluoromethylthiolation of ethyl formylacetate was reported by
Haas in 1971,[7] a group of CF3S-N[8] or CF3S-O[9] based
electrophilic trifluoromethylthiolating reagents have been
developed
and
achieved
great
success
in
the
trifluoromethylthiolation of keto-esters, ketones and aldehydes by
independent research groups. In 2018, Besset et al. reported the
electrophilic trifluoromethylthiolation of α-chloroaldehydes using
Munavalli reagent as the SCF3 source, which could construct a
quaternary carbon center containing both a chlorine and a SCF3
group next to the aldehyde group (Scheme 1, eq. 1).[10] However,
chlorinated aldehydes are needed as substrates in the reaction and
[a]
D. -W. Sun, Dr. M. Jiang,* Prof. J.-T. Liu*
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry, University of Chinese Academy
of Science, Chinese Academy of Science
345 Lingling Road, Shanghai 200032 (China)
Fax: (+)86-21-64166128
Scheme 1. Previous work and this work.
E-mail: jtliu@sioc.ac.cn, jiangmin@sioc.ac.cn
Homepage: http://liujintao.sioc.ac.cn/
trifluoromethylthiolation methods with easily available and cheap
reagents, it was found that the trifluoromethylthiolation-based
bifunctionalization of -diketones could be achieved with
CF3SOCl (Scheme 1, eq. 3). The results are reported in this paper.
Supporting information for this article is available on the WWW under
http://www.chemeurj.org/ or from the author.
1
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10.1002/chem.201901781
Chemistry - A European Journal
14
15
16
17
18
19
20
21
22
23d
24e
NaHCO3
NaOH
1:3.0:3.0
1:3.0:3.0
1:3.0:3.0
1:3.0:3.0
1:3.0:3.0
1:3.0:3.0
1:3.0:3.0
1:3.0:3.0
1:3.0:3.0
1:3.0:3.0
1:1.5:3.0
DCM
DCM
DCM
toluene
THF
0
0
In our preliminary experiments, 1,3-diphenylpropane-1,3-
dione (1a) was chosen as the substrate. In the presence of pyridine,
the reaction of 1a with CF3SOCl (1.5 equiv.) was carried out in
dichloromethane (DCM) at room temperature. Gratefully, 19F
NMR monitoring indicated that a new compound containing
trifluoromethylthio group was formed although the yield was only
14%. After the isolation and characterization of this product, it
was confirmed that the bifunctionalization reaction of 1a occurred
K3PO4
0
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
trace
trace
trace
trace
36
DMF
DMSO
CH3CN
DCE
to
give
the
corresponding
product,
2-chloro-2-
trifluoromethylthio-1,3-diphenylpropane-1,3-dione (2a) (Table 1,
entry 1). Inspired by the result, we screened different conditions
next to find a suitable protocol for the selective formation of 2a.
Investigating the ratio of reactants found that increasing the
amount of CF3SOCl or base was beneficial for the
bifunctionalization reaction (entries 2-6). With a ratio of 1:3.0:3.0
(1a/CF3SOCl/pyridine), the yield of 2a could be improved to 74%
(entry 5). Control experiments indicated that base was important
for the reaction (entry 7). So we studied the base effect further.
However, various organic bases, such as triethylamine (Et3N),
triisopropylamine (iPr3N), N-methylpiperidine and piperidine,
could not improve the yield of 2a (entries 8-11), and inorganic
bases (Na2CO3, K2CO3, NaHCO3, NaOH, K3PO4) failed to
promote this bifunctionalization reaction with full recovery of 1a
(entries 12-16). Therefore, pyridine was chosen as the base to
further study the solvent effect. It was found that much lower
yields were obtained with toluene, tetrahydrofuran (THF), N,N-
dimethylformamide (DMF) or dimethyl sulfoxide (DMSO)
(entries 17-20). Acetonitrile and dichloroethane were also less
effective for the reaction (entries 21-22). DCM was the best
solvent for this reaction among all solvents tested. Furthermore,
decreasing the temperature to 0 oC lowered the yield of 2a to 70%
(entry 23). Thus, the optimal conditions were set to 3.0 equivalent
of CF3SOCl, 3.0 equivalent of pyridine in DCM at room
temperature. It is worth mentioning that the bifunctionalization
reaction of 1a with CF3SO2Na in the presence of POCl3 also
occurred and 2a was obtained in 68% yield (entry 24).
27
DCM
DCM
70
68
[a] Reaction conditions: 1a (0.4 mmol), CF3SOCl (0.6-1.2 mmol), base (0.4-
1.6 mmol), solvent (1 mL), room temperature. [b] Isolated yield. [c] Reaction
time was 12 h. [d] The reaction was carried out at 0 oC. [e] CF3SO2Na (0.6
mmol) was used instead of CF3SOCl in the presence of POCl3 (1.2 mmol).
With the optimized reaction conditions in hand, we studied the
scope of -diketones for this bifunctionalization reaction. As
shown in Scheme 2, a range of 1,3-diarylpropane-1,3-diones 1
with different substituents in the phenyl group reacted readily
with CF3SOCl and gave the expected products in moderate to good
yields. -Diketones containing both electron-rich and electron-
deficient phenyl group were compatible with the reaction
conditions. With -diketones bearing a methoxy or methyl
substituent, the reaction gave the bifunctionalization product in
good yields (2b-2c, 2h-2i). -Diketones containing halide or
cyano substitutent also reacted well to give the desired products
2d-2g in moderate yields. Good yields were also achieved when
-ketoesters were used as substrates (2j-2m). In addition, the
reactions of alkylated -diketones such as 1-phenylbutane-1,3-
dione, 1-phenylpentane-1,3-dione and heptane-3,5-dione were
also examined, and the corresponding bifunctionalization
products 2n-2p were obtained in good yields (81%-84%).
Having achieved the trifluoromethylthiolation of diketones, we
further tried their perfluoroalkylthiolation reaction. Considering
perfluoroalkanesulfinyl chlorides could be made from sodium
perfluoroalkanesulfinates (RfSO2Na), and CF3SO2Na/POCl3
system could also promote the above bifunctionalization reaction
(Table 1, entry 23), sodium perfluoroalkanesulfinate, such as
ClCF2CF2SO2Na, n-C4F9SO2Na and n-C6F13SO2Na, was used
directly as the perfluoroalkylthiolation reagent. Fortunately, the
reaction worked well in the presence of POCl3 under similar
conditions, giving the corresponding perfluoroalkylthiolated
bifunctionalization products 2q-2s in moderate yields.
Table 1 Optimization of the reaction conditions
entrya
base
ratio
solvent yield(%)b
(1a:CF3SOCl:base)
1
2
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
-
1:1.5:1.0
1:2.0:1.0
1:2.0:2.0
1:3.0:2.5
1:3.0:3.0
1:3.0:4.0
1:3.0:0
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
14
18
33
50
74
45
NR
56
47
46
3
Interestingly, when 1-(2-hydroxyphenyl)-3-phenylpropane-1,3-
dione (3a), an aromatic 1,3-diketone in which a phenyl group
contains a hydroxyl substituent at the orth-position, was used to
react with CF3SOCl under the optimized conditions, 3-
((trifluoromethyl)thio)-4H-chromen-4-one (4a) was formed in
72% yield in stead of the expected bifunctionalization product.
From the structure of 4a, it is obvious that the reaction involved a
4
5
6
7c
8
Et3N
iPr3N
1:3.0:3.0
1:3.0:3.0
1:3.0:3.0
trifluoromethylthiolation/cyclization process. As
a class of
9
important compounds, flavone and its derivatives have attracted
significant attention recently due to their presence in many
pharmaceutically active natural products.[16] They are also useful
synthetic intermediates.[17] Therefore, the introduction of the SCF3
group into flavones is very desirable and may give new bioactive
compounds with unique properties. So we next studied the scope
of -diketones 3 containing a phenyl group with an orth-hydroxyl
10
N-
Methylpiperidine
11
12
13
piperidine
1:3.0:3.0
1:3.0:3.0
1:3.0:3.0
DCM
DCM
DCM
0
0
0
Na2CO3
K2CO3
2
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10.1002/chem.201901781
Chemistry - A European Journal
Scheme 3 The intramolecular trifluoromethylthiolation/cyclization
reaction of 3
substituent in this trifluoromethylthiolation/cyclization reaction.
As shown in Scheme 3, the substituent in phenyl group R2, either
electron-donating or electron-withdrawing, had a little influence
on the yield of 4. For example, the reaction of -diketones 3b-e
bearing a methyl or methoxyl substituent gave the corresponding
products 4b-e in 70-75% yields. For substrates 3f-i with a halide
or trifluoromethyl substituent in phenyl group, products 3f-i were
obtained in 62-68% yields. Moderate yields were achieved with
-diketones 3j-k containing a meta-methyl or meta-methoxyl
O
O
O
SRf
R2
pyridine
R2
R1
+
[RfSOCl]
R1
DCM, rt, 10 min
O
OH
4
3
O
O
O
SCF3
SCF3
SCF3
C6H5
O
C6H4Me-o
O
C6H4Me-p
O
a
a
a
4c
, 75%
4b
, 71%
4a
, 72%
Scheme 2. Scope of the bifunctionalization reaction of 1
O
O
O
O
SCF3
SCF3
SCF3
C6H4Cl-p
O
C6H4OMe-o
O
C6H4Me-m
4f, 66%a
a
a
4e
, 70%
4d
, 72%
O
O
O
SCF3
SCF3
SCF3
O
O
O
O
O
O
p-MeOC6H4
C6H5
Cl SCF3
O
C6H4CF3-p
O
C6H4F-
a
p
C6H5
C6H5
Cl SCF3
p-MeC6H4
p-ClC6H4
p-tBuC6H4
C6H5
Cl SCF3
2b, 76%a
O
C6H4Br-p
4i, 62%a
a
4g
, 67%
4h
, 68%
2c, 81%a
2a, 74%a, 68%b
O
O
O
O
O
O
O
O
O
SCF3
C6H5
SCF3
C6H5
SCF3
p-BrC6H4
C6H5
Cl SCF3
p-FC6H4
C6H5
Cl SCF3
C6H5
Cl SCF3
O
O
O
Me
a
a
a
2d, 73%a
2f, 68%a
4l
, 54%
4j
, 69%
2e, 71%a
4k
, 67%
O
O
O
O
O
O
O
O
O
O
O
SCF3
SCF2CF2Cl
p-MeOC6H4
C6H4OMe-p
Cl SCF3
SC4F9
SC6F13
C6H5
C6H4OMe-p
Cl SCF3
2h, 84%a
p-NCC6H4
C6H5
Cl SCF3
2g, 70%a
2i, 79%a
O
furyl-2
C6H5
b
O
C6H5
b
O
a
4n
, 61%
b
4m
, 64%
4o
, 47%
4p
, 50%
O
O
O
O
O
O
C6H5
OEt
Cl SCF3
[a] Reaction conditions: 1 (0.4 mmol), CF3SOCl (1.2 mmol), pyridine (1.2
mmol), DCM (1.0 mL), rt, 10 min, under N2, isolated yield. [b] Reaction
conditions: 1 (0.4 mmol), RfSO2Na (0.6 mmol), POCl3(1.2 mmol), pyridine
(1.2 mmol), DCM (1.0 mL), rt, 10 min, under N2, isolated yield.
p-CF3C6H4
OEt
Cl SCF3
p-MeOC6H4
OEt
Cl SCF3
2k, 82%a
2l, 70%a
2j, 75%a
O
O
O
O
O
O
C6H5
Me
Cl SCF3
p-FC6H4
OEt
Cl SCF3
2m, 73%a
C6H5
Et
Cl SCF3
2n, 81%a
2o,84%a
O
O
O
O
O
O
O
O
C6H5
C6H5
Cl SCF2CF2Cl
C6H5
C6H5
Cl SC6F13
Et
Et
C6H5
C6H5
Cl SC4F9
Cl SCF3
2s, 50%b
2p, 82%a
2q, 60%b
2r, 54%b
[a] Reaction conditions: 1 (0.4 mmol), CF3SOCl (1.2 mmol), pyridine (1.2
mmol), DCM (1.0 mL), rt, 10 min, under N2, isolated yield. [b] Reaction
conditions: 1 (0.4 mmol), RfSO2Na (0.6 mmol), POCl3 (1.2 mmol), pyridine
(1.2 mmol), DMF (1.0 mL), rt, 10 min, under N2, isolated yield.
Figure 1. ORTEP Drawing of 4j
We also studied the reaction of -diketones 5 containing a
phenyl group with an orth-amino substituent, similar compounds
to -diketones 3 in which the hydroxyl group was changed to
NHTs, with CF3SOCl under the standard conditions. The
trifluoromethylthiolation/cyclization reaction also occurred.
However, trifluoromethylthio-substituted indolin-3-ones 6 were
obtained in moderate yields, indicating that different reaction
pathway was involved (Scheme 4). Again, the electronic property
of the aryl group had a light effect on the reaction.
substituent to the hydroxyl group. In the case of R2 = methyl or
furyl, the reaction also worked to give the desired products 4l-4m
in moderate yields. In addition, this protocol is also applicable to
RfSO2Na/POCl3 system. Under similar conditions, the reactions
of 3a with RfSO2Na such as ClCF2CF2SO2Na, n-C4F9SO2Na and
n-C6F13SO2Na in the presence of POCl3 took place readily to give
the corresponding perfluoroalkylthiolation/cyclization products
4n-4p in moderate yields (Scheme 3). The structure of compound
4 was determined by spectroscopy analysis and further confirmed
by X-Ray diffraction experiments of 4j (see Figure 1 and the
Supporting Information)18.
3
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10.1002/chem.201901781
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Scheme 4 The intramolecular trifluoromethylthiolation/cyclization
reaction of 5
sodium
perfluoroalkanesulfinate/POCl3
system.
Having
advantages including cheap reagent, mild conditions, easy-to-
handle, short reaction time, transition-metal-free and the ability to
construct a multifunctional SCF3-containing quaternary carbon
center or a chromone motif in one step, this protocol is expected
to find applications in organic synthesis and drug development.
As
a
comparison, the reaction of 1a with sodium
was studied, but the expected
methanesulfinate
bifunctionalization product 7 was obtained in only 29% yield
(Scheme 5).
Scheme 5. Reaction of 1a with sodium methanesulfinate
Based on the experimental results and literature reports,[15,19]
a
plausible mechanism was proposed for above reactions as showed
in Scheme 6. The reaction of 1 and base affords anion
intermediate A, which reacts with CF3SOCl to give compound B.
In the presence of excess CF3SOCl, B might react with another
CF3SOCl to form cation intermediate C. Due to the activation of
carbonyl groups and sulphur cation, the second proton of
methylene group in intermediate C could be easily removed in the
presence of base, resulting in the formation of species D.
Subsequent nucleophilic attack of Cl- on the carbon of C=S gives
final product, 2-chloro-2-trifluoromethylthio--diketone 2. When
there is an orth-amino group in the phenyl group, intramolecular
nuclephilic attack of nitrogen atom is more favourable and cyclic
product 6 is formed as the final product. While in the case of
hydroxyl, anion intermediate E may be formed from intermediate
C in the presence of base, and undergoes nucleophilic attack of
oxygen anion on the C=O bound to give intermediate F.
Subsequent nucleophilic attack of oxygen anion on the S=O
bound in F and ring-opening transformations gives compound 4
as the final product.
Scheme 6. Proposed mechanism for the bifunctionalization reaction of -
diketones.
Experimental Section
General procedure for the trifluoromethylthiolation: To a solution of -diketone
1a (or 3a, 0.4 mmol) and CF3SOCl (1.2 mmol, 3.0 equiv) in DCM (1.0 mL) was
added pyridine (1.2 mmol, 3.0 equiv) dropwise over a period of 1 min. The mixture
was stirred at room temperature. After the reaction was completed (monitored by
TLC), dilute hydrochloric acid was added to quench the reaction. The resulting
mixture was extracted with DCM for three times (3 x 8.0 mL) and the combined
organic solution was dried over Na2SO4 and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel (petroleum
ether/DCM=10/1~5:1 v/v) to give the corresponding product 2a (or 4a).
General procedure for the perfluoroalkylthiolation: To a solution of -diketone
1a (or 3a, 0.4 mmol), pyridine (1.2 mmol, 3.0 equiv) and ClCF2CF2SO2Na (0.6
mmol, 1.5 equiv) in DMF (or DCM, 1.0 mL) was added POCl3 (1.2 mmol, 3.0 equiv)
dropwise over a period of 1 min. The mixture was stirred at room temperature. After
the reaction was completed (monitored by TLC), dilute hydrochloric acid was added
to quench the reaction. The resulting mixture was extracted with DCM for three
times (3 x 8.0 mL) and the combined organic solution was dried over Na2SO4 and
concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel (petroleum ether/DCM=10/1~5:1 v/v) to give the
corresponding product 2q (or 4n).
In conclusion, we have demonstrated a novel method for the
trifluoromethylthiolation-based bifunctionalization of activated
methylene
trifluoromethylthiolating reagent. In the presence of base, -
diketones and -ketoesters reacted readily with
with
cheap
and
easily
available
trifluoromethanesulfinyl chloride to give the corresponding -
trifluoromethylthiolated -chloro--diketones and -chloro--
ketoesters, respectively. When -diketones containing a phenyl
group with an orth-hydroxyl or orth-amino substituent were used
as substrates, cyclic products, trifluoromethylthiolated 4H-
chromen-4-one and indolin-3-one, were formed through an
intramolecular trifluoromethylthiolation/cyclization process. The
method can also be extended to perfluoroalkylthiolation with
Acknowledgements
Financial support from the National Natural Science Foundation of China (No.
21572257) is gratefully acknowledged.
4
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10.1002/chem.201901781
Chemistry - A European Journal
Eur. J. Org. Chem. 2015, 4607. d) L. Hu, M. Wu, H. Wan, J. Wang, G. Wang,
H. Guo, S. Sun, New J. Chem. 2016, 40, 6550.
Keywords:
trifluoromethylthiolation,
-diketone,
bifunctionalization, cyclization, trifluoromethanesulfinyl
chloride, perfluoroalkylthiolation
[9]
X. Shao, X. Wang, T. Yang, L. Lu, Q. Shen, Angew. Chem., Int. Ed. 2013, 52,
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[10] F. Gelat, T. Poisson, A. T. Biju, X. Pannecoucke, T. Besset, Eur. J. Org.
Chem. 2018, 3693.
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5
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10.1002/chem.201901781
Chemistry - A European Journal
trifluoromethylthiolation 
Dong-Wei Sun, Min Jiang,* and
Jin-Tao Liu* _____ Page – Page
Novel
Activated
Bifunctionalization
Methylene:
of
Base-
Promoted
Trifluoromethylthiolation of -
Diketones
Trifluoromethanesulfinyl
Chloride
with
A
novel bifunctionalization of
A
series
of
-chloro--
activated methylene was achieved trifluoromethylthio--diketones and
through
trifluoromethylthiolation
diketones
the
based-promoted trifluoromethylthiolated
cyclic
- products were obtained in moderate to
with good yields under mild conditions.
of
trifluoromethanesulfinyl chloride.
6
This article is protected by copyright. All rights reserved.