Radical Difluororomethylation of Thiols with Difluoromethylphosphonium Triflate under Photoredox Catalysis

Article abstract of DOI:10.1021/acs.joc.7b01041

A convenient, visible light-induced radical difluoromethylation of aryl-, heteroaryl-, and alkylthiols with difluoromethyltriphenylphosphonium triflate was developed to afford various difluoromethyl thioethers in moderate to excellent yields. The key reaction features include the use of a readily available CF₂H radical source, mild reaction conditions, and excellent chemoselective thiol-difluoromethylation.

Full text of DOI:10.1021/acs.joc.7b01041

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Article
Radical Difluroromethylation of Thiols with
Difluoromethylphosphonium Triflate under Photoredox Catalysis
Yang Ran, Qing-Yu Lin, Xiu-Hua Xu, and Feng-Ling Qing
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01041 • Publication Date (Web): 28 Jun 2017
Downloaded from http://pubs.acs.org on June 28, 2017
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Radical Difluroromethylation of Thiols with
Difluoromethylphosphonium Triflate under Photoredox
Catalysis
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Yang Ran,† Qing-Yu Lin,† Xiu-Hua Xu,† and Feng-Ling Qing*,†,‡
†Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
‡College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North
Renmin Lu, Shanghai 201620, China
Eꢀmail: flq@mail.sioc.ac.cn
Table of Graphic Contents
Abstract
A convenient, visible lightꢀinduced radical difluoromethylation of arylꢀ, heteroarylꢀ, and alkylthiols
with difluoromethyltriphenylphosphonium triflate was developed to afford various difluoromethyl
thioethers in moderate to excellent yields. The key reaction features include the use of a readily available
CF2H radical source, mild reaction conditions and excellent chemoselective thiolꢀdifluoromethylation.
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Introduction
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As an important type of fluorineꢀcontaining groups, fluoroalkylthio groups have received growing
interest over the past few years.1 The association of fluoroalkyl groups with sulfur atom generally
increases the lipophilicity parameter of these substituents. In particular, the trifluoromethylthio group
(SCF3) has extremely high Hansch parameter (πR = 1.44).2 Thus, it is not surprising to witness the surge
in the number of methods for introduction of SCF3 into organic compounds recently.3 Compared to
SCF3, its analogous difluoromethylthio group (SCF2H) is less lipophilic, but gains additional hydrogenꢀ
bond donor capabilities.4 Consequently, SCF2H essentially serves as a lipophilic hydrogenꢀbond donor
motif for drug discovery, and the SCF2H substituent has emerged as an important functional group in
bioactive molecules, such as pyriprole and flomoxef sodium (Figure 1).5
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Figure 1. SCF2Hꢀcontaining bioactive compounds
Traditionally, the difluoromethylthiolated compounds are prepared by the reaction of thiol (thiolate)
or derivative with difluorocarbene in situꢀgenerated from the ozoneꢀdepleting compound HCF2Cl.6
Recently, impressive advances have been made for the synthesis of these compounds,7 involving either
C─SCF2H8 or CS─CF2H9ꢀ13 bond formation. The direct difluoromethylthiolation (C─SCF2H bond
formation) of widely available substrates such as halides, boronic acids, carboxylic acids, and amines
with the difluoromethylthiolating reagents has emerged as powerful approaches to various
difluoromethyl thioethers.8 However several steps were required for the preparation of
difluoromethylthiolating reagents. The new methods for CS─CF2H bond formation can be classified
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into four reaction types: difluorocarbeneꢀmediated reactions,9 electrophilic,11 nucleophilic,12 and
radical13 difluoromethylation. First, new difluorocarbene precursors were developed to make the
traditional method more environmentally benign.9 Even so, this protocol suffers from the low
chemoselectivity when two or more nucleophilic groups exist in the substrate.10 The electrophilic
difluoromethylation of sulfurꢀcontaining compounds gave difluoromethyl thioethers only in moderate
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yields.11
Difluoromethyl thioethers were formed in high yields from the nucleophilic
difluoromethylation of disulfides,12 but half of the disulfides were wasted in these processes. Baran and
coꢀworkers reported that the radical difluromethylation of heteroarylthiols with Zn(SO2CF2H)2 in the
presence of tꢀBuOOH gave the corresponding difluoromethyl thioethers in moderate yield (Scheme
1a).13a Yi developed a silverꢀcatalyzed radical difluoromethylation of arylꢀ and heteroarylthiols with
NaSO2CF2H using K2S2O8 as oxidant (Scheme 1b).13b Recently, photoredox catalysis has been regarded
as a valuable and environmentally benign tool in organic synthesis.14 Our group very recently disclosed
the radical difluoromethylation of alkenes with difluoromethylphosphonium salts under photoredox
catalysis.15 Compared to other CF2H radical sources, difluoromethylphosphonium salts are more easily
available and handled.16 Herein, we disclose a complementary visible lightꢀinduced radical
difluoromethylation of thiols with difluoromethyltriphenylphosphonium triflate (Scheme 1c). This
method provides a new access to difluoromethyl thioethers using easily available difluoromethylating
reagent under mild conditions.
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Scheme 1. Radical Difluoromethylation of Thiols
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Results and Discussion
Initially, we chose 4ꢀ(tertꢀbutyl)benzenethiol (1a) as the model substrate to optimize the reaction
conditions (Table 1). In our previous studies,15b,c it was found that among the common photocatalysts
only facꢀIr(ppy)3 was capable of reduction of difluoromethylphosphonium salt to CF2H radical. Thus,
facꢀIr(ppy)3 was chosen as the photocatalyst for
difluoromethylation of 1a with
difluoromethylphosphonium salts (2aꢀd) in the presence of tetramethylethylenediamine (TMEDA) using
MeCN as the solvent under visible light irradiation (entries 1ꢀ4). Among the
difluoromethylphosphonium salts tested, difluoromethylphosphonium triflate (2b) afforded the desired
difluoromethyl thioether 3a in highest yield (entry 2). Then, switching TMEDA to other additives
including NaHCO3, 1,8ꢀdiazobicyclo[5,4,0]undecꢀ7ꢀene (DBU), NEt3, N,Nꢀdimethylaniline, and N,Nꢀ
dimethylꢀ4ꢀtoluidine led to lower yields (entries 5ꢀ9). It was noteworthy that product 3a was formed in
32% yield even in the absence of an additive (entry 10). Subsequently, different solvents including DMF,
DMSO, THF, and acetone were investigated (entries 11ꢀ14). However, no higher yield was obtained.
Finally, the yield of 3a was increased by prolonging the reaction time and increasing the amount of
difluoromethylating reagent (entries 15 and 16). An excess of difluoromethylphosphonium triflate (2b)
was required for formation of 3a in high yield, because part of 2b was converted into CF2H2 under these
reaction conditions. Compound 3a was not formed when the reaction was performed in the absence of
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photoredox catalyst or visible light (entries 17 and 18), which indicated that both the photoredox catalyst
and visible light were crucial for this reaction.
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Table 1. Optimization of Reaction Conditions for Difluoromethylation of Arylthiol a
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entry 2 (X)
Additive
Solvent
yield (%)b
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2a (Br)
TMEDA
TMEDA
TMEDA
TMEDA
NaHCO3
DBU
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
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2b (OTf)
2c (BF4)
2d (PF6)
2b (OTf)
2b (OTf)
2b (OTf)
2b (OTf)
2b (OTf)
2b (OTf)
2b (OTf)
2b (OTf)
2b (OTf)
2b (OTf)
2b (OTf)
2b (OTf)
2b (OTf)
2b (OTf)
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NEt3
8
N,Nꢀdimethylaniline
N,Nꢀdimethylꢀ4ꢀtoluidine
─
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15c
16d
17e
18f
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
DMSO
THF
Acetone
MeCN
MeCN
MeCN
MeCN
72
85
0
0
aReaction conditions: 1a (0.1 mmol), difluoromethyltriphenylphosphonium salt (0.3 mmol), facꢀ
b
Ir(ppy)3 (0.003 mmol), additive (0.2 mmol), solvent (1.0 mL), visible light, rt, under N2, 24 h. Yields
determined by 19F NMR spectroscopy using fluorobenzene as an internal standard. c48 h.
dDifluoromethyltriphenylphosphonium salt (0.4 mmol). eIn the absence of facꢀIr(ppy)3. fIn the dark.
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With optimized conditions in hand, the substrate scope of arylthiols was investigated (Scheme 2).
The electronꢀneutral, electronꢀrich, and electronꢀdeficient arylthiols (1aꢀl) reacted with
difluoromethylphosphonium 2b to afford the corresponding aryl difluoromethyl thioethers (3aꢀl) in good
to excellent yields. An array of functional groups including ether, alcohol, phenol, amine, amide,
chloride, bromide, nitrile, and ester were well tolerated under the mild conditions. It is noteworthy that
difluoromethylation of (4ꢀmercaptophenyl)methanol (1c) and 4ꢀmercaptophenol (1d) with 4.0 equiv. of
2b gave only Sꢀdifluoromethylated products (3c and 3d). No Oꢀdifluoromethylated product was detected.
This excellent chemoselectivity highlights the unique property of the current method, which is different
from the difluorocarbeneꢀbased protocols.9 The sterically hindered arylthiol (1l) also proceeded
smoothly to give product 3l in 88% yield. However, low yield was obtained when naphthaleneꢀ2ꢀthiol
was subjected to the standard conditions.
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Scheme 2. Difluoromethylation of Arylthiolsa
visible light
fac-Ir(ppy)3 (3 mol %)
SH
SCF2H
TfO CF2H
P
+
R
R
TMEDA, MeCN
Ph
Ph
Ph
1
3
SCF2H
SCF2H
SCF2H
HO
tBu
MeO
O
3a, 86%
SCF2H
3b, 93%
3c, 71%
SCF2H
SCF2H
HO
Cl
N
N
H
3d, 87%
SCF2H
3e, 85%
3f, 83%
SCF2H
SCF2H
Br
F3C
3g, 82%
SCF2H
3h, 83%
3i, 72%
Cl
SCF2H
SCF2H
Cl
NC
MeO2C
3j, 90%
3k, 78%
3l, 88%
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aReaction conditions: 1 (0.5 mmol), difluoromethyltriphenylphosphonium triflate (2.0 mmol), facꢀ
Ir(ppy)3 (0.015 mmol), TMEDA (1.0 mmol), MeCN (5.0 mL), visible light, rt, under N2, 48 h. Yields
are those of the isolated products.
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We next turned our attention to the difluoromethylation of heteroarylthiols for the preparation of
heteroaryl difluoromethylthioethers. Compared to the difluoromethylation of 4ꢀ(tertꢀbutyl)benzenethiol
(1a), the reaction of benzo[d]thiazoleꢀ2ꢀthiol (4a) was faster and required less
difluoromethylphosphonium (2b) (Table 2, entry 1). After screening of the additives and solvents
(entries 2ꢀ8), the difluoromethylated product (5a) was obtained in up to 92% yield in the presence of
N,Nꢀdimethylꢀ4ꢀtoluidine using DMF as the solvent (entry 6). This is due to the solubility of the
substrate in DMF.
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Table 2. Screening of Additives and Solvents for Difluoromethylation of Heteroarylthiola
Entry
Additive
Solvent
yield (%)b
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7
8
TMEDA
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
68
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42
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92
81
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NEt3
DBU
N,Nꢀdimethylaniline
N,Nꢀdimethylꢀ4ꢀtoluidine
N,Nꢀdimethylꢀ4ꢀtoluidine
N,Nꢀdimethylꢀ4ꢀtoluidine
N,Nꢀdimethylꢀ4ꢀtoluidine
DMSO
THF
aReaction conditions: 4a (0.1 mmol), difluoromethyltriphenylphosphonium triflate (0.3 mmol), facꢀ
b
Ir(ppy)3 (0.003 mmol), additive (0.2 mmol), solvent (1.0 mL), visible light, rt, under N2, 24 h. Yields
determined by 19F NMR spectroscopy using fluorobenzene as an internal standard.
The optimized reaction conditions (Table 2, entry 6) were suitable for the conversion of a series of
heteroarylthiols to the corresponding difluoromethyl thioethers in moderate to excellent yields (Scheme
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3). Benzo[d]thiazoleꢀ2ꢀthiols (4aꢀf) bearing electronꢀwithdrawing and electronꢀdonating groups were
well tolerated. Moreover, the difluoromethylation of 4ꢀthiopyridine (4g), 2ꢀthiopyridine (4h), and 2ꢀ
thiopyrimidine (4i) occurred in excellent yields. In all cases, only Sꢀdifluoromethylated products were
obtained and no Nꢀdifluoromethylated product was detected.10
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Scheme 3. Difluoromethylation of Heteroarylthiols
aReaction conditions: 4 (0.5 mmol), difluoromethyltriphenylphosphonium triflate (1.5 mmol), facꢀ
Ir(ppy)3 (0.015 mmol), N,Nꢀdimethylꢀ4ꢀtoluidine (1.0 mmol), DMF (5.0 mL), visible light, rt, under N2,
24 h. Yields are those of the isolated products.
The alkylthiols are challenging substrates for the radical difluoromethylation process. Benzylthiol 6a
and alkylthiol 6b were respectively converted into difluoromethyl thioethers 7a and 7b in low yields
(Scheme 4). These results are consistent with the analogous radical trifluoromethylation of alkylthiols.17
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Scheme 4. Difluoromethylation of Alkyl Thiols
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To gain insight into the reaction mechanism, 2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy (TEMPO), a well
known radical scavenger, was added into the standard reaction conditions of 1a. The desired product 3a
was not obtained and a TEMPOꢀCF2H adduct 8 was formed (Scheme 5a). This result provides
supportive evidence that a CF2H radical may be involved as a reactive species in this reaction. Moreover,
in some cases, the formation of disulfides in the reaction mixture was detected. Thus, the
difluoromethylation of disulfide 918 under the standard reaction conditions was investigated, and
difluoromethylated product 3a was also obtained in high yield (Scheme 5b). Additionally, the
fluorescence quenching experiments at different concentration of difluoromethylphosphonium 2b
showed that 2b exhibited fluorescence quenching of excited state *facꢀIrIII(ppy)3 (see the Supporting
Information). This result suggested that electron transfer probably occurred from *facꢀIrIII(ppy)3 to 2b
firstly.
Scheme 5. Mechanistic Experiments
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Based on the above results, a proposed mechanism for the reaction is outlined in Scheme 6. First,
irradiation with visible light excites facꢀIrIII(ppy)3 into *facꢀIrIII(ppy)3, which is then oxidized by
difluoromethylphosphonium 2b via a single electron transfer (SET) to give facꢀIrIV(ppy)3 and CF2H
radical. Subsequently, CF2H radical reacts with thiolate affording the corresponding radical anion
intermediate, which undergoes a SET to give the final product difluoromethyl thioether (path a). On the
other hand, thiolate might be oxidized by facꢀIrIV(ppy)3 to sulfur radical, which is easily converted into
the disulfide. The reaction of CF2H radical and disulfide could also give the difluoromethyl thioether
(path b). The excellent chemoselective thiolꢀdifluoromethylation suggest that path b is the more likely
reaction pathway, although path a can not be ruled out. However, the exact reaction mechanism remains
unclear at the moment.
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Scheme 6. Proposed Reaction Mechanism
*fac-IrIII(ppy)3
CF2H
TfO
visible light
P
Ph
Ph
Ph
2b
fac-IrIV(ppy)3
fac-IrIII(ppy)3
+
CF2H
TfO
R3N
R3N
R3N
RSH
RS
RSCF2H
RSCF2H
path a
path b
RS
fac-IrIII(ppy)3
fac-IrIV(ppy)3
RSSR
CF2H
visible light
2b
*fac-IrIII(ppy)3
Conclusion
We have developed an efficient and practical radical difluoromethylation of arylꢀ, heteroarylꢀ, and
alkylthiols with readily available difluoromethyltriphenylphosphonium triflate by visible light
photoredox catalysis. This protocol provides an attractive approach to a range of difluoromethyl
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thioethers under mild conditions with excellent S/X (X = O, N)ꢀselectivities. Further exploration of the
reaction mechanism and the application of this method are underway in our laboratory.
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Experimental Section
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General Experimental Methods. 1H NMR (TMS as the internal standard) and 19F NMR spectra (CFCl3
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13
as the outside standard and low field is positive) were recorded on a 400 MHz spectrometer. C NMR
was recorded on 400 MHz spectrometer. Chemical shifts (δ) are reported in ppm, and coupling constants
(J) are in Hertz (Hz). The following abbreviations were used to explain the multiplicities: s = singlet, d
= doublet, t = triplet, q = quartet, m = multiplet. HRMS data using EI were obtained on a GCꢀTOF mass
spectrometer. Unless otherwise noted, all reagents were obtained commercially and used without further
purification. Substrates were purchased from commercial sources or were prepared according to
literature procedures.
General procedure for difluoromethylation of aryl thiols
A 50 mL Schlenk flask equipped with a rubber septum and a magnetic stir bar was charged with
difluoromethyltriphenylphosphonium triflate 2b (925.0 mg, 2.0 mmol, 4.0 equiv.) and facꢀIr(ppy)3 (9.8
mg, 0.015 mmol, 3 mol%). Then thiol 1 (0.5 mmol, 1.0 equiv.), TMEDA (0.15 mL, 1.0 mmol, 2.0
equiv.),and MeCN (5 mL) was added. The flask was sealed with 3M vinyl electrical tape. The mixture
was degassed three times by the freezeꢀpumpꢀthaw procedure. The flask was placed at a distance of 2
cm from the blue LEDs. The mixture was stirred under nitrogen atmosphere and irradiated by blue 30 W
LEDs for 48 h. After the reaction was complete, 10% H2O2 (5 mL) was added to the reaction mixture
(Note: H2O2 was used to oxidize PPh3 to Ph3PO for the purification of the desired products easier). The
reaction mixture was extracted by Et2O. The organic phase was dried by anhydrous sodium sulfate,
concentrated in vacuo, and the residue was purified with silica gel column chromatography to provide
the desired product.
(4-(Tert-butyl)phenyl)(difluoromethyl)sulfane (3a). Compound 3a was obtained as a light yellow liquid
1
(93.4 mg, 86%), hexane/Et2O = 9:1 as eluent for the column chromatography. H NMR (400 MHz,
CDCl3) δ ppm 7.51 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 6.80 (t, J = 57.2 Hz, 1H), 1.33 (s, 9H);
13C NMR (100 MHz, CDCl3) δ ppm 153.2, 135.2, 126.5, 122.5 (t, J = 3.0 Hz), 121.2 (t, J = 274.1 Hz),
37.8, 31.2; 19F NMR (376 MHz, CDCl3) δ ppm ꢀ91.4 (d, J = 57.2 Hz, 2F); MS (EI): m/z 216 (M+).
These data matched with the reported results.8b
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(Difluoromethyl)(4-methoxyphenyl)sulfane (3b). Compound 3b was obtained as a yellow liquid (88.6
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mg, 93%), hexane as eluent for the column chromatography. H NMR (400 MHz, CDCl3) δ ppm 7.49ꢀ
7.51 (m, 2H), 6.89ꢀ6.91 (m, 2H), 6.73 (t, J = 57.2 Hz, 1H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
ppm 161.2, 137.6, 121.0 (t, J = 273.3 Hz), 116.1 (t, J = 3.0 Hz), 114.9, 55.3; 19F NMR (376 MHz,
CDCl3) δ ppm ꢀ92.3 (d, J = 57.5 Hz, 2F); MS (EI): m/z 190 (M+). These data matched with the reported
results.8b
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(4-((Difluoromethyl)thio)phenyl)methanol (3c). Compound 3c was obtained as a yellow liquid (67.9
mg, 71%), DCM/MeOH = 50:1 as eluent for the column chromatography. 1H NMR (400 MHz, CDCl3)
δ ppm 7.53 (d, J = 8.0 Hz, 2H), 7.32(d, J = 8.0 Hz, 2H), 6.79 (t, J = 56.8 Hz, 1H), 4.62 (s, 2H), 2.61ꢀ
2.68 (m, 1H); 13C NMR (100 MHz, CDCl3) δ ppm 142.7, 135.6, 127.6, 124.8 (t, J = 3.0 Hz), 121.8 (t, J
= 273.3 Hz), 64.3; 19F NMR (376 MHz, CDCl3) δ ppm ꢀ91.5 (d, J = 57.2 Hz, 2F); IR (thin film) ν 3341,
2926, 1492, 1320, 1297, 1067, 817 cmꢀ1; MS (EI): m/z 190 (M+); HRMS (EIꢀTOF): m/z [M+] Calculated
for C8H8F2OS: 190.0264; Found: 190.0267.
4-((Difluoromethyl)thio)phenol (3d). Compound 3d was obtained as a light brown liquid (76.9 mg,
1
87%), hexane/EA = 5:1 as eluent for the column chromatography. H NMR (400 MHz, CDCl3) δ ppm
7.45 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.73 (t, J = 57.2 Hz, 1H), 5.34ꢀ5.39 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ ppm 157.3, 137.9, 120.9 (t, J = 274.1 Hz), 116.4; 19F NMR (376 MHz,
CDCl3) δ ppm ꢀ92.3 (d, J = 57.2 Hz, 2F); MS (EI): m/z 176 (M+). These data matched with the reported
results.13b
N-(4-((difluoromethyl)thio)phenyl)acetamide (3e). Compound 3e was obtained as a light yellow solid
1
(92.6 mg, 85%), hexane/EA = 1:1 as eluent for the column chromatography. H NMR (400 MHz, d6ꢀ
DMSO) δ ppm 10.1 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.32 (t, J = 56.4 Hz, 1H),
2.04 (s, 3H); 13C NMR (100 MHz, d6ꢀDMSO) δ ppm 169.1, 141.5, 136.6, 121.4 (t, J = 271.8 Hz), 120.0,
118.3 (t, J = 3.1 Hz), 24.4; 19F NMR (376 MHz, d6ꢀDMSO) δ ppm ꢀ92.9 (d, J = 56.0 Hz, 2F); MS (EI):
m/z 217 (M+). These data matched with the reported results.8b
4-((Difluoromethyl)thio)-N,N-dimethylaniline (3f). Compound 3f was obtained as a light brown liquid
1
(84.7 mg, 83%), hexane/Et2O = 9:1 as eluent for the column chromatography. H NMR (400 MHz,
CDCl3) δ ppm 7.42 (d, J = 9.2 Hz, 2H), 6.69 (t, J = 57.6 Hz, 1H), 6.66 (d, J = 8.8 Hz, 2H), 2.98 (s, 6H);
13C NMR (100 MHz, CDCl3) δ ppm 151.5, 137.4, 121.4 (t, J = 273.3 Hz), 112.5, 109.8 (t, J = 3.1 Hz),
40.1; 19F NMR (376 MHz, CDCl3) δ ppm ꢀ92.6 (d, J = 57.2 Hz, 2F); MS (EI): m/z 203 (M+). These data
matched with the reported results.8a
(4-Chlorophenyl)(difluoromethyl)sulfane (3g). Compound 3g was obtained as a colorless liquid (79.6
1
mg, 82%), hexane as eluent for the column chromatography. H NMR (400 MHz, CDCl3) δ ppm 7.49ꢀ
7.52 (m, 2H), 7.34ꢀ7.37 (m, 2H), 6.79 (t, J = 56.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ppm 136.7,
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136.5, 129.6, 124.2 (t, J = 3.0 Hz), 120.3 (t, J = 274.8 Hz); 19F NMR (376 MHz, CDCl3) δ ppm ꢀ91.7 (d,
J = 56.0 Hz, 2F); MS (EI): m/z 194 (M+). These data matched with the reported results.8b
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(4-Bromophenyl)(difluoromethyl)sulfane (3h). Compound 3h was obtained as a light yellow liquid
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(98.7 mg, 83%), hexane/Et2O = 9:1 as eluent for the column chromatography. H NMR (400 MHz,
CDCl3) δ ppm 7.42ꢀ7.52 (m, 4H), 6.79 (t, J = 56.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ppm 136.9,
132.6, 124.9 (t, J = 3.0 Hz), 124.7, 120.2 (t, J = 274.1 Hz); 19F NMR (376 MHz, CDCl3) δ ppm ꢀ91.7 (d,
J = 56.0 Hz, 2F); MS (EI): m/z 238 (M+). These data matched with the reported results.8b
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(Difluoromethyl)(4-(trifluoromethyl)phenyl)sulfane (3i). Compound 3i was obtained as a light yellow
liquid (82.1 mg, 72%), pentane as eluent for the column chromatography. 1H NMR (400 MHz, CDCl3) δ
ppm 7.68 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 6.87 (t, J = 56.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ ppm 134.9, 131.7 (q, J = 32.6 Hz), 130.9, 126.1 (q, J = 3.8 Hz), 123.7 (q, J = 271.1 Hz), 120.1
(t, J = 274.8 Hz); 19F NMR (376 MHz, CDCl3) δ ppm ꢀ63.0 (s, 3F), ꢀ91.3 (d, J = 55.6 Hz, 2F); MS (EI):
m/z 228 (M+). These data matched with the reported results.9f
4-((Difluoromethyl)thio)benzonitrile (3j). Compound 3j was obtained as a colorless liquid (83.5 mg,
90%), hexane/Et2O = 9:1 as eluent for the column chromatography. 1H NMR (400 MHz, CDCl3) δ ppm
13
7.64 (s, 4H), 6.89 (t, J = 56.0 Hz, 1H); C NMR (100 MHz, CDCl3) δ ppm 134.5, 132.7, 119.7 (t, J =
19
275.6 Hz), 117.9, 113.2; F NMR (376 MHz, CDCl3) δ ppm ꢀ91.3 (d, J = 56.0 Hz, 2F); MS (EI): m/z
185 (M+). These data matched with the reported results.8b
Methyl 4-((difluoromethyl)thio)benzoate (3k). Compound 3k was obtained as a light yellow liquid
1
(85.3 mg, 78%), hexane/EA = 5:1 as eluent for the column chromatography. H NMR (400 MHz,
CDCl3) δ ppm 8.00 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 6.87 (t, J = 56.4 Hz, 1H), 3.90 (s, 3H);
13C NMR (100 MHz, CDCl3) δ ppm 166.2, 134.0, 132.2 (t, J = 3.0 Hz), 131.0, 130.3, 120.4 (t, J = 274.1
Hz), 52.3; 19F NMR (376 MHz, CDCl3) δ ppm ꢀ91.2 (d, J = 57.2 Hz, 2F); MS (EI): m/z 218 (M+). These
data matched with the reported results.8b
(2,6-Dichlorophenyl)(difluoromethyl)sulfane (3l). Compound 3l was obtained as a light yellow liquid
(100.6 mg, 88%), hexane as eluent for the column chromatography. 1H NMR (400 MHz, CDCl3) δ ppm
7.44 (d, J = 8.0 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H), 6.88 (t, J = 57.6 Hz, 1H); 13C NMR (100 MHz,
19
CDCl3) δ ppm 142.5, 132.0, 129.0, 125.1 (t, J = 3.8 Hz), 120.1 (t, J = 277.1 Hz); F NMR (376 MHz,
CDCl3) δ ppm ꢀ92.0 (d, J = 58.7 Hz, 2F); MS (EI): m/z 228 (M+). These data matched with the reported
results.9c
General procedure for difluoromethylation of heteroaryl thiols
A 50 mL Schlenk flask equipped with a rubber septum and a magnetic stir bar was charged with
difluoromethyltriphenylphosphonium triflate 2b (690.0 mg, 1.5 mmol, 3.0 equiv.) and facꢀIr(ppy)3 (9.8
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mg, 0.015 mmol, 3 mol%). Then thiol 4 (0.5 mmol, 1.0 equiv.), N,Nꢀdimethyꢀ4ꢀtoluidine (0.14 mL, 1.0
mmol, 2.0 equiv.),and DMF (5 mL) was added. The flask was sealed with 3M vinyl electrical tape. The
mixture was degassed three times by the freezeꢀpumpꢀthaw procedure. The flask was placed at a
distance of 2 cm from the blue LEDs. The mixture was stirred under nitrogen atmosphere and irradiated
by blue 30 W LEDs for 24 h. After the reaction was complete, 10% H2O2 (5 mL) was added to the
reaction mixture. The reaction mixture was extracted by Et2O. The organic phase was dried by
anhydrous sodium sulfate, concentrated in vacuo, and the residue was purified with silica gel column
chromatography to provide the desired product.
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2-((Difluoromethyl)thio)benzo[d]thiazole (5a). Compound 5a was obtained as a light yellow liquid
1
(100.2 mg, 90%), hexane/DCM = 10:1 as eluent for the column chromatography. H NMR (400 MHz,
CDCl3) δ ppm 7.98 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 7.2 Hz, 1H), 7.63 (t, J = 56.0 Hz, 1H), 7.46ꢀ7.50 (m,
13
1H), 7.37ꢀ7.41 (m, 1H); C NMR (100 MHz, CDCl3) δ ppm 157.0, 152.9, 135,9, 126.6, 125.6, 122.8,
121.2, 120.3 (t, J = 275.6 Hz); 19F NMR (376 MHz, CDCl3) δ ppm ꢀ93.2 (d, J = 56.0 Hz, 2F); MS (EI):
m/z 217 (M+). These data matched with the reported results.9c
6-Chloro-2-((difluoromethyl)thio)benzo[d]thiazole (5b). Compound 5b was obtained as a light yellow
1
liquid (107.2 mg, 85%), hexane/DCM = 10:1 as eluent for the column chromatography. H NMR (400
MHz, CDCl3) δ ppm 7.96 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.65 (t, J = 56.0 Hz, 1H), 7.37 (d, J = 8.8 Hz,
13
1H); C NMR (100 MHz, CDCl3) δ ppm 159.5, 153.6, 134.0, 132.8, 126.0, 122.6, 121.8, 120.0 (t, J =
276.4 Hz); 19F NMR (376 MHz, CDCl3) δ ppm ꢀ93.5 (d, J = 55.6 Hz, 2F); IR (thin film) ν 1547, 1430,
1287, 1064, 997, 801, 780 cmꢀ1; MS (EI): m/z 251 (M+); HRMS (EIꢀTOF): m/z [M+] Calculated for
C8H4ClF2NS2: 250.9442; Found: 250.9438.
6-Bromo-2-((difluoromethyl)thio)benzo[d]thiazole (5c). Compound 5c was obtained as a yellow liquid
1
(137.7 mg, 93%), hexane/DCM = 10:1 as eluent for the column chromatography. H NMR (400 MHz,
13
CDCl3) δ ppm 8.09ꢀ8.10 (m, 1H), 7.63ꢀ7.66 (m, 1H), 7.65 (t, J = 56.0 Hz, 1H), 7.46ꢀ7.49 (m, 1H); C
NMR (100 MHz, CDCl3) δ ppm 157.0, 152.9, 135,9, 126.6, 125.6, 122.8, 121.2, 120.3 (t, J = 275.6 Hz);
19F NMR (376 MHz, CDCl3) δ ppm ꢀ93.2 (d, J = 56.0 Hz, 2F); IR (thin film) ν 1542, 1462, 1427, 1287,
1071, 997, 893, 780 cmꢀ1; MS (EI): m/z 295 (M+); HRMS (EIꢀTOF): m/z [M+] Calculated for
C8H4BrF2NS2: 294.8937; Found: 294.8936.
4-Bromo-2-((difluoromethyl)thio)-6-(trifluoromethyl)benzo[d]thiazole (5d). Compound 5d was
obtained as a yellow liquid (151.5 mg, 83%), hexane/DCM = 10:1 as eluent for the column
1
chromatography. H NMR (400 MHz, CDCl3) δ ppm 8.02 (s, 1H), 7.88 (s, 1H), 7.80 (t, J = 55.6 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ ppm 162.7, 152.8, 136.1, 128.5 (q, J = 33.4 Hz), 127.1 (q, J = 6.1
Hz), 123.0 (q, J = 271.8 Hz), 119.9 (t, J = 276.4 Hz), 117.8 (q, J = 4.6 Hz), 116.5; 19F NMR (376 MHz,
CDCl3) δ ppm ꢀ61.7 (s, 3F), ꢀ93.9 (d, J = 55.6 Hz, 2F); IR (thin film) ν 1460, 1391, 1306, 1170, 1134,
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1087, 1009, 880 cmꢀ1; MS (EI): m/z 363 (M+); HRMS (EIꢀTOF): m/z [M+] Calculated for C9H3BrF5NS2:
362.8810; Found: 362.8809.
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2-((Difluoromethyl)thio)-6-nitrobenzo[d]thiazole (5e). Compound 5e was obtained as a light yellow
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solid (85.3 mg, 65%), hexane/DCM = 1:1 as eluent for the column chromatography. MP: 94ꢀ95 C. H
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NMR (400 MHz, CDCl3) δ ppm 8.74ꢀ8.75 (m, 1H), 8.33ꢀ8.36 (m, 1H), 8.02ꢀ8.05 (m, 1H), 7.78 (t, J =
13
55.6 Hz, 1H); C NMR (100 MHz, CDCl3) δ ppm 164.9 (t, J = 3.8 Hz), 156.2, 145.0, 135.8, 122.7,
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122.2, 119.7 (t, J = 276.3 Hz), 117.7; 19F NMR (376 MHz, CDCl3) δ ppm ꢀ93.9 (d, J = 54.5 Hz, 2F); IR
(thin film) ν 1597, 1515, 1431, 1324, 1076, 1028, 1004, 741 cmꢀ1; MS (EI): m/z 262 (M+); HRMS (EIꢀ
TOF): m/z [M+] Calculated for C8H4F2N2O2S2: 261.9682; Found: 261.9677.
2-((Difluoromethyl)thio)-6-ethoxybenzo[d]thiazole (5f). Compound 5f was obtained as a light yellow
solid (111.3 mg, 85%), hexane/DCM = 1:1 as eluent for the column chromatography. MP: 44ꢀ46 oC. 1H
NMR (400 MHz, CDCl3) δ ppm 7.87 (d, J = 8.8 Hz, 1H), 7.45(t, J = 56.4 Hz, 1H), 7.24 (d, J = 2.4 Hz,
1H), 7.07 (dd, J = 2.8 Hz, J = 8.8 Hz, 1H), 4.06 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ ppm 157.5, 147.5, 138.0, 125.7, 123.6, 120.3 (t, J = 276.4 Hz), 116.5, 104.2, 64.1,
12.7; 19F NMR (376 MHz, CDCl3) δ ppm ꢀ92.7 (d, J = 55.6 Hz, 2F); IR (thin film) ν 1600, 1470, 1448,
1258, 1225, 1084, 998, 822 cmꢀ1; MS (EI): m/z 261 (M+); HRMS (EIꢀTOF): m/z [M+] Calculated for
C10H9F2NOS2: 261.0094; Found: 261.0089.
4-((Difluoromethyl)thio)pyridine (5g). Compound 5g was obtained as a brown liquid (54.5 mg, 67%),
1
hexane/EA = 1:1 as eluent for the column chromatography. H NMR (400 MHz, CDCl3) δ ppm 8.53ꢀ
8.55 (m, 2H), 7.35ꢀ7.36 (m, 2H), 6.95 (t, J = 55.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ppm 150.2,
19
138.4, 126.2, 119.7 (t, J = 274.9 Hz); F NMR (376 MHz, CDCl3) δ ppm ꢀ91.2 (d, J = 55.6 Hz, 2F);
MS (EI): m/z 161 (M+). These data matched with the reported results.8a
2-((Difluoromethyl)thio)pyridine (5h). Compound 5h was obtained as a brown liquid (73.0 mg, 91%),
1
hexane/EA = 10:1 as eluent for the column chromatography. H NMR (400 MHz, CDCl3) δ ppm 8.45ꢀ
13
8.46 (m, 1H), 7.68(t, J = 56.4 Hz, 1H), 7.55ꢀ7.59 (m, 1H), 7.22ꢀ7.24 (m, 1H), 7.10ꢀ7.13 (m, 1H); C
NMR (100 MHz, CDCl3) δ ppm 153.1 (t, J = 3.1 Hz), 150.1, 137.1, 124.3 (t, J = 2.3 Hz), 121.7, 121.3 (t,
19
J = 269.5 Hz); F NMR (376 MHz, CDCl3) δ ppm ꢀ96.3 (d, J = 56.0 Hz, 2F); MS (EI): m/z 161 (M+).
These data matched with the reported results.8a
2-((Difluoromethyl)thio)-4,6-dimethylpyrimidine (5i). Compound 5i was obtained as a brown liquid
1
(89.2 mg, 94%), hexane/EA = 10:1 as eluent for the column chromatography. H NMR (400 MHz,
CDCl3) δ ppm 7.81 (t, J = 56.0 Hz, 1H), 6.78 (s, 1H), 2.39 (s, 6H); 13C NMR (100 MHz, CDCl3) δ ppm
167.8, 166.4, 121.2 (t, J = 268.0 Hz), 117.4, 23.7; 19F NMR (376 MHz, CDCl3) δ ppm ꢀ99.1 (d, J = 55.6
Hz, 2F); MS (EI): m/z 190 (M+). These data matched with the reported results.9f
General procedure for difluoromethylation of alkyl thiols
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A 50 mL Schlenk flask equipped with a rubber septum and a magnetic stir bar was charged with
difluoromethyltriphenylphosphonium triflate 2b (690.0 mg, 1.5 mmol, 3.0 equiv.) and facꢀIr(ppy)3 (9.8
mg, 0.015 mmol, 3 mol%). Then thiol 6 (0.5 mmol, 1.0 equiv.), DBU (0.15 mL, 1.0 mmol, 2.0 equiv.),
and DMSO (5 mL) was added. The flask was sealed with 3M vinyl electrical tape. The mixture was
degassed three times by the freezeꢀpumpꢀthaw procedure. The flask was placed at a distance of 2 cm
from the blue LEDs. The mixture was stirred under nitrogen atmosphere and irradiated by blue 30 W
LEDs for 48 h. After the reaction was complete, 10% H2O2 (5 mL) was added to the reaction mixture.
The reaction mixture was extracted by Et2O. The organic phase was dried by anhydrous sodium sulfate,
concentrated in vacuo, and the residue was purified with silica gel column chromatography to provide
the desired product.
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Benzyl(difluoromethyl)sulfane (7a). Compound 7a was obtained as a light yellow liquid (32.5 mg,
37%), hexane/DCM = 5:1 as eluent for the column chromatography. 1H NMR (400 MHz, CDCl3) δ ppm
13
7.28ꢀ7.35 (m, 5H), 6.73 (t, J = 56.4 Hz, 1H), 4.02 (s, 2H); C NMR (100 MHz, CDCl3) δ ppm 136.2,
19
128.9, 128.8, 128.5, 128.3, 127.7, 120.2 (t, J = 271.1 Hz), 31.7 (t, J = 3.8 Hz); F NMR (376 MHz,
CDCl3) δ ppm ꢀ94.5 (d, J = 56.0 Hz, 2F); MS (EI): m/z 174 (M+). These data matched with the reported
results.9c
Benzyl(difluoromethyl)sulfane (7b). Compound 7b was obtained as a light yellow liquid (39.4 mg,
42%), hexane/DCM = 5:1 as eluent for the column chromatography. 1H NMR (400 MHz, CDCl3) δ ppm
7.32ꢀ7.35 (m, 2H), 7.22ꢀ7.28 (m, 3H), 6.78 (t, J = 56.4 Hz, 1H), 2.97ꢀ3.09 (m, 4H); 13C NMR (100
19
MHz, CDCl3) δ ppm 139.6, 128.6, 128.6, 126.7, 120.6 (t, J = 271.8 Hz), 36.8, 28.6 (t, J = 3.0 Hz); F
NMR (376 MHz, CDCl3) δ ppm ꢀ92.7 (d, J = 56.0 Hz, 2F); MS (EI): m/z 188 (M+). These data matched
with the reported results.8a
Acknowledgment
This work was supported by the National Natural Science Foundation of China (21421002, 21332010)
and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20000000,
XDB20020000).
Supporting Information Available: Preliminary mechanistic experiments, as well as copies of 1H, 19F,
and 13C NMR spectra. These material are available free of charge via the Internet at http://pubs.acs.org.
References
(1) For selected reviews, see: (a) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem., Int. Ed. 2013, 52,
8214. (b) Chu, L.; Qing, F.ꢀL. Acc. Chem. Res. 2014, 47, 1513. (c) Toulgoat, F.; Alazet, S.; Billard,
T. Eur. J. Org. Chem. 2014, 2415. (d) Xu, X.ꢀH.; Matsuzaki, K.; Shibata, N. Chem. Rev. 2015, 115,
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