Novel usage of 2-BTSO2CF2H for metal-free electrophilic difluoroalkanethiolation of indoles

Article abstract of DOI:10.1039/d0ob00872a

The electrophilic difluoromethylthiolation of indoles with 2-BTSO2CF2H is developed. In the presence of (EtO)2P(O)H and TMSCl, the reaction proceeded under mild conditions to give products in modest to high yields. This is a new application of 2-BTSO2CF2H for electrophilic difluoromethylthiolation.

Full text of DOI:10.1039/d0ob00872a

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DOI: 10.1039/D0OB00872A
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Novel Usage of 2-BTSO2CF2H for Metal-Free Electrophilic
Difluoroalkanethiolation of Indoles
Received 00th January
Jun Weia, Kun Baoa,b, Yuan Wanga, Rong Shenga*, Jinbo Huc*
20xx,
Accepted 00th January
20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
incompatibility of the harsh thermal and strongly basic reaction
conditions to generate reactive thiolates and “CF2” species.
Electrophilic difluoromethylthiolation of indoles with 2-BTSO2CF2H
is developed. In the presence of (EtO)2P(O)H and TMSCl, the
reaction proceeded under mild conditions to give products in
modest to high yields. This is a new application of 2-BTSO2CF2H for
electrophilic difluoromethylthiolation.
Fig.
1 -SCF2H containing bioactive compounds and direct
difluoromethylthiolating reagents.
NC
SCF2H
N
In recent years, the introduction of -SCF2H group into organic
molecule has been of growing interest in pharmaceutical and
agrochemical fields1. The -SCF2H possesses moderate lipophilicty (πR
= 0.68 for -SCF2H, 0.56 for -CH3 and 1.44 for -SCF3)2 as well as
unique properties. (1) -SCF2H is considered as an enhanced version
of CF3 and a lipophilic OH or NH surrogate for bioactive molecules.
(2) -SCF2H can serve as a weak hydrogen bond donor with slightly
acidic proton. (3) Incorporation of -SCF2H group into drugs often
significantly improves their metabolic stability3. For example,
Pyriprole, an EP approved novel pesticide for animals, the
introduction of -SCF2H moiety at pyrozole ring is beneficial to
activity4. In addition, the important role of -SCF2H in
pharmaceuticals and agrochemicals is evidenced by its frequent
enrolment in other bioactive compounds, e.g., nifedipine analogue5,
herbicide SSH-1086, and thymol analogue7 (Fig. 1).
H
N
N
H
Cl
HF2CS
N
N
SCF2H
N
SCF2H
CO2Me
Cl
N
N
MeO2C
HO
NH
N
CF3
H
Pyriprole
Pesticide
Nifedipine analogue
Treatment of hypertension
SSH-108
Herbicide
Thymol analogue
Anti-infective
difluoromethylthiolating reagents
O
Ph
I
O
O
S
N
SCF2H
SCF2H
SO2CF2H
O
N
Ag SCF2H
O
N
1b
HCF2SO2Na
1e
1c
1d
S
HCF2SO2Cl
HCF2SOCl
SO2CF2H
N
1h
1f
1g
1a
this work
Recently, many efficient direct methods to introduce -SCF2H
group directly into molecule have been disclosed. In 2015，Shen
and co-workers demonstrated the copper-promoted Sandmeyer
difluoro-methylthiolation of aryl and heteroaryl diazonium salts
using the first nucleophilic difluoromethylthiolating reagent, N-
heterocyclic carbene (NHC) ligated difluoromethylthiolated silver
complex [(SIPr)Ag(SCF2H)]13 (Fig. 1, 1a). Complementarily, the same
group also developed the N-difluoromethylthiophthalimide 1b as a
new electrophilic difluoromethylthiolating reagent14. In addition, S-
(difluoromethyl) benzenesulfonothioate 1c was also developed as a
robust radical difluoromethylthiolating reagent by Shen and Li
groups 15. Recently, a key “in situ reduction” concept was made by
Shibata et al. who delineated the difluoromethanesulfonyl (-SO2
CF2H) hypervalent iodonium ylides 1d as electrophilic difluoro-
methylthiolating reagents for various of nucleophiles16. Based on
this strategy, HCF2SO2Na17 1e, HCF2SO2Cl18 1f and HCF2SOCl19 1g
also been reported as novel electrophilic difluoromethylthiolating
reagents under reductive conditions.
The prevalent methods for the construction of the -SCF2H moiety
involve the insertion of in situ generated CF2 carbene into RS-H
bond using reagents such as ClCF2H8, ClCF2CO2Na9, TMSCF2Br10,
PhS(O)(NTs)CF2H11 and Ph3P+CF2CO2− 12. Nevertheless, these indirect
methods suffer from the limited availability of the thiol substrates,
a. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058,
People’s Republic of China;
b. Collaborative Innovation Center of Yangtze River Delta Region Green
Pharmaceuticals, Zhejiang University of Technology, Hangzhou, 310014, P. R.
China
c. Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai, 200032,
People’s Republic of China
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Hu and co-workers focused on the research of fluoroalkyl PymSO2CF2H 1i, 2-PySO2CF2H 1j, PhSO2CF2H 1k (entries 5-7).
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heteroaryl sulfones for many years20, and developed a bench-stable, Especially, the first reduction potential of several difluoromethyl
DOI: 10.1039/D0OB00872A
readily
available
reagent,
2-((difluoromethyl)sulfonyl)- sulfones (1h: -1.17 V; 1i: -1.35 V; 1j: -1.47 V; 1k: -1.77 V; versus the
benzo[d]thiazole (2-BTSO2CF2H, 1h), which can undergo a radical saturated calomel electrode, SCE) are consistent with their reaction
difluoromethylation on various isocyanides under visible light 21, as efficiency20. Then, the pivotal role played by TMSCl was illustrated
well as can serve as difluoroalkanesulfinate precursor22. Recently, by the control experiment as the TMSCl free conditions disabled the
we disclosed the trifluoromethylsulfinylation of electron-rich arenes reaction completely (entries 8-10). Furthermore, the employment
under reductive conditions using 2-BTSO2Rf (Rf = CF3, C4F9, CF2Br, of Ph2P(O)Cl or Ph2PCl as reductant cannot improve the yield of
CF2Cl, CF2CO2Et) as RfSO synthons and Ph2P(O)Cl as the reducing product either (entries 11-12). Therefore, the best result was
agent. This is the first example that 2-BTSO2Rf perform as the RfSO obtained with a combination of indole and 1a (1.5 equiv.) with
source in organic synthesis via both C(Het)-S and S=O bond (EtO)2P(O)H (3.0 equiv.), TMSCl (3.0 equiv.) in MeCN at 80°C for 4 h
cleavage23. Inspired by this work, we try to apply a similar strategy to furnish 3a in 74% yield (entry 2).
and achieve the direct difluoromethylthiolation of indoles with 2-
BTSO2CF2H.
Table 2. Fluoromethylthiolation of indolesa
SCF2H
R3
N
R2
Table 1. Reaction optimizationa
S
N
(EtO)2P(O)H
R3
R1
SO CF H
R1
+
2
2
SCF2H
TMSCl
MeCN
N
P reagent
R2
+
1h
2
3
(Het)Ar-SO2CF2H
℃
solvent, 80
N
H
N
H
Br
SCF2H
SCF2H
SCF2H
SCF2H
1
2a
3a
Br
SO2CF2H
N
H
S
N
N
N
N
SO2CF2H
SO2CF2H
SO2CF2H
F
H
H
H
N
N
N
3c
3d
3h
3a
3b
, 67%
, 82%
, 71%
, 63%
SCF2H
SCF2H
O
SCF2H
SCF2H
2-PymSO2CF2H 2-PySO2CF2H
PhSO2CF2H
2-BTSO2CF2H
1h
_1.17 V
1i
1j
1k
,
_1.35 V
,
_1.47 V
,
_1.77 V
,
N
H
N
H
N
H
N
O
H
Entry P reagent
Additive
1
Solvent
3ab
3e,
3f
3g, 50%
, 67%
66%
, 63%
1
56
74
49
35
24
0
(EtO)2P(O)H
(EtO)2P(O)H
(EtO)2P(O)H
(EtO)2P(O)H
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
-
1h
1h
1h
1h
1i
toulene
MeCN
DMF
SCF2H
CN
SCF2H
O
B
SCF2H
NH
2
O
N
N
H
3
4
THF
3i
3k
, 53%
, 64%
3j
, 33%
O
N
O
O
SCF2H
5
(EtO)2P(O)H
(EtO)2P(O)H
(EtO)2P(O)H
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
SCF2H
SCF2H
N
N
6
1j
O
N
N
N
N
H
H
H
7
0
1k
1h
1h
1h
1h
1h
3l,
3m,
3n,
64%
74%
O
72%
8
0
(EtO)2P(O)H
(EtO)2P(O)H
(EtO)2P(O)H
Ph2P(O)Cl
Ph2PCl
SCF2H
N
N
H
N
N
N
N
O
9
0
H
TBAC
HCl
HN
O
SCF2H
44%
SCF3
N
10
11
12
0
HN
HN
3p,
N
3o,
nemiralisib
SCF2Cl
67%
34
32
-
O
SCF3
-
O
SCF2H
aReaction conditions: 1 (0.3 mmol), 2a (0.2 mmol), P reagent (0.6
mmol), additive (0.6 mmol), solvent (1 mL), N2, 80 ℃, 4 h. Yields
were determined by 19F NMR using PhCF3 as an internal standard.
N
O
N
N
N
H
H
H
b
b
c
3q
3r',
, 58%
43%
3r,
3s,
23%
33%
aReaction conditions: 1 (1.5 mmol, 1.5 equiv), 2 (1.0 mmol, 1.0
equiv), (EtO)2P(O)H (3.0 mmol, 3.0 equiv.), TMSCl (3.0 mmol, 3.0
equiv.), MeCN (5 mL), N2, 80 ℃ for 4 h. Isolated yields. b 2-BTSO2CF3
was used. c 2-BTSO2CF2Cl was used.
Our initial attempt began by employing indole 2a as the model
substrate with 2-BTSO2CF2H (1h, 1.1 equiv) and (EtO)2P(O)H/TMSCl
in toluene (1.0 mL) at 80 °C under an inert atmosphere17.
Gratifyingly, the desired difluoromethylthiolation product 3a was
isolated in 56% yield (entry 1). Subsequent solvent screening
revealed that MeCN was more favorable than toluene, DMF and
THF (entries 2-4). And no better results were obtained using other
difluoromethyl 2-heteroaryl sulfone reagents, including 2-
With optimized reaction conditions in hand, we explored the
substrate scope with various indole derivatives, and the results are
summarized in Table 2. The substrates with simple functional
groups (such as halogen, alkyl, alkoxy) in different sites of indole
2 | J. Name., 2012, 00, 1-3
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were the suitable substrates for this transformation and gave the (EtO)2P(O)-OS(O)CF3 is more inclined to be attacked by indole, thus
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DOI: 10.1039/D0OB00872A
corresponding products 3a−3i in moderate to excellent yields obtaining the CF3S(O) decorated product.
(50−82%), while the 7-cyano indole 2j afford the desired products
Scheme 2. In suit 19F NMR analysis
3j in poor yield (33%), probabaly due to the steric effect. This
method tolerates indoles that contain various functional groups,
including borate 2k, isoxazole 2l, dibasic chain 2m, morpholino
methanone 2n and carbamate 2o, and affording the corresponding
target compounds in moderate to good yields (3k-3o). The reaction
of 1h with 6-(1H-indol-4-yl)-1H-indazole 2p, the active skeleton of
selective PI3Kδ inhibitor nemiralisib,24 only gave the 3-
difluoromethylthiolated indole 3p, indicating the excellent
selectivity between indole and carbazole under the standard
conditions. Reaction with electron-rich substituted pyrrole also can
produce the corresponding difluoromethylthiolated product 3q in
58% yield. In addition, trifluoromethylthiolation and halodifluoro-
methylthiolation of indole can be achieved in moderate yields by
using 2-BTSO2CF3 and 2-BTSO2CF2Cl as fluorine source. Notably, The
2-BTSO2CF3 formed the two products 3r and 3r' in yields of 33% and
43%, respectively. The structure of 3k was confirmed by single
crystal X-ray analysis (see the SI)25.
SCF2H
O
S
S
N
(EtO)2P(O)H
+
CF2H
TMSCl, MeCN
PhCF3(IS), 80oC
N
N
F
O
F
H
H
1h
2d
3d
5.5 h
4 h
3d
-F
1.5 h
0 min
HCF2S(O)H
1h
-CF2H
2d
-F
Scheme 1. Preliminary mechanistic study
Scheme 3. Proposed mechanism
O
S
S
N
(EtO)2P(O)H
S
CF2H
Cl
(EtO)2P(O)
S
CF2H
CF2H
+
+
S
TMSCl, PhCF3 (IS)
N
O
P
O
Cl
O
O
N
1h
73%
O
O
S
N
S
N
(EtO)2P(O)H
TMSCl
SCF2H
S
CF2H
S
CF2H
O
S
S
N
indole
(EtO)2P(O)H
(EtO)2P(O)
S
O
CF2H
O
O
TMSCl, PhCF3 (IS)
A
N
1
O
Cl
H
(EtO)2P(O)-O-S-CF2H
73%
1h
0%
B
S(O)-O
To get insight into the mechanism of this transformation, a
control reaction was conducted and monitored by 19F NMR. First, 2-
BTSO2CF2H 1h was subjected to the reaction conditions in the
absence of indole, (EtO)2P(O)-SCF2H (δ = 87.47 ppm) was obtained
in 73% yield with a quantitative amount of 2-chlorobenzothiazole.
Thereafter, indole 2a was subjected to the above mixture, and
surprisingly, with or without heating, the corresponding targeted
molecule 3a cannot be detected, which indicated that (EtO)2P(O)-
SCF2H is not the reactive species for this transformation (Scheme 1).
Then, an in suit 19F NMR analysis of this transformation was
conducted using 1h and 2d as reactants (Scheme 2, see the SI for
details). The reagent 1h (−123.3 ppm) promptly disappeared within
1.5 h at 80℃, and small friable signals appeared between −118.5
and −123.0 ppm, which is believed to be HCF2S(O)H according to
previous report.26
(EtO)2P(O)-OH
homolysis
O
indole
TMSCl
3
HCF2S OH
HCF2SH
HCF2S Cl
E
D
C
O
Nuc
Nuc
SCF3
O
(EtO)2P(O)H
main
2-BTSO2CF3
(EtO)2P(O)-O-S-CF3
TMSCl
CF3S(O)H
homolysis
Conclusions
In conclusion, 2-BTSO2CF2H/(EtO)2P(O)H/TMSCl system has been
used for the metal free electrophilic difluoromethylthiolation of
various indoles in moderate to good yields. This is the first time to
report 2-BTSO2CF2H as a -SCF2H synthon in organic synthesis. The
mechanism study shows that HCF2S(O)H probably acts as the
reactive intermediate instead of (EtO)2P(O)-SCF2H.
On the basis of the above results and the literature, a plausible
mechanism for this reaction was proposed as follow (Scheme 3).
First, the oxygen of 2-BTSO2CF2H attack the phosphorus center of
(EtO)2P(O)H to get intermediate A, which is converted to
(EtO)2P(O)-OS(O)CF2H B through eliminating 2-chlorobenzo[d]-
thiazole. The S(O)-O homolysis of (EtO)2P(O)-OS(O)CF2H gave
(EtO)2P(O)-OH (detected by LCMS) and the key Intermediate
HCF2S(O)H C followed by an intramolecular nucleophilic collapse to
form HCF2SOH D25. Then, HCF2SOH D directly converts to HCF2SCl E
in the presence of TMSCl for directly difluoromethylthiolation. In
the case of 2-BTSO2CF3, compared with the S(O)-O homolysis,
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21672187, 21632009, 21421002,
21472221), Zhe Jiang Natural Science Foundation
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(LZ17H300002), the National Basic Research Program of China
(2015CB931900), the Key Programs of the Chinese Academy of
Sciences (KGZD-EW-T08), the Key Research Program of
Frontier Sciences of CAS (QYZDJ-SSW-SLH049).
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for this paper. These data can be obtained free of charge from
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DOI: 10.1039/D0OB00872A
Tables of Contents Entry
2-BTSO2CF2H was used as an efficient electrophilic -SCF2H synthon in the first time for the metal-
free electrophilic difluoromethylthiolation of indoles.