Radical Aromatic Trifluoromethylthiolation: Photoredox Catalysis vs. Base Mediation

Article abstract of DOI:10.1002/ejoc.201701339

Trifluoromethyl aryl sulfides (Ar-SCF₃) constitute highly attractive building blocks due to their exceptional lipophilicity and chemical properties. Related protocols of radical aromatic trifluoro-methylthiolation of arenediazonium salts were developed that are based on the facile generation of intermediate aryl radicals. Their reactions with commercial F₃CS-SCF₃ under very mild conditions afforded a diverse set of Ar-SCF₃ (< 90 % yield). Direct comparison of photoredox catalysis {eosin Y or [Ru(bpy)₃]Cl₂} with the weak base-mediated dark reaction documented higher synthetic efficiency of the former but higher operational simplicity of the latter strategy.

Full text of DOI:10.1002/ejoc.201701339

A Journal of
Accepted Article
Title: Radical Aromatic Trifluoromethylthiolation: Photoredox Catalysis
vs. Base Mediation
Authors: Axel Jacobi von Wangelin, Denis Koziakov, and Michal Majek
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European Journal of Organic Chemistry
10.1002/ejoc.201701339
COMMUNICATION
Radical Aromatic Trifluoromethylthiolation: Photoredox Catalysis
vs. Base Mediation
[a]
[a]
[a],[b]
Denis Koziakov, Michal Majek, and Axel Jacobi von Wangelin*
Abstract: Trifluoromethyl aryl sulfides (Ar-SCF
3
) constitute highly
ammonium trifluoromethyl thiolates are commonly employed as
SCF nucleophiles.
attractive building blocks due to their exceptional lipophilicity and
chemical properties. Related protocols of radical aromatic trifluoro-
methylthiolation of arenediazonium salts were developed that are
based on the facile generation of intermediate aryl radicals. Their
3
reactions with commercial F
afforded a diverse set of Ar-SCF
photoredox catalysis (eosin Y or [Ru(bpy)
3
CS-SCF
(<90% yield). Direct comparison of
]Cl ) with the weak base-
3
under very mild conditions
3
3
2
mediated dark reaction documented higher synthetic efficiency of the
former but higher operational simplicity of the latter strategy.
Introduction
Even though fluorine containing compounds are the least spread
1
among naturally occurring organic halides, fluorine-containing
substituents have recently emerged as a widespread and
2
3
significant component in pharmaceuticals, agrochemicals and
4
materials . Beside the introduction of fluorides, trifluoromethyl,
3
and other perfluoroalkyl units, the trifluoromethylsulfanyl (SCF )
group has attracted great attention for its exceptional physical
and chemical properties. Several well-known drugs, comprising
5
Scheme 1. Important synthesis routes to aryl trifluoromethyl sulfides.
SCF
group (SCF
electron-withdrawing substituent that imparts very high
lipophilicity to an organic molecule. Despite its polarity ( =0.48,
cf. 0.23 (Cl), 0.53 (CF ), 0.66 (CN)), SCF exhibits the highest
Hansch lipophilicity constant among standard heteroatomic
organic substituents (π =1.44, cf. 0.88 (CF ), 0.14 (F), 1.68
tBu)). The synthetic procedures for the decoration of arenes
3
, are depicted in the Scheme 1. The trifluoromethylsulfanyl
3
) is a chemically stable, relatively polar and strongly
We have recently reported on the photoredox-catalyzed
synthesis of arylsulfides from arenediazonium salts and
disulfides in the presence of eosin Y under green light irradiation
p
3
3
1
3
(
Scheme 2, top). Later, we have developed a weak base-
p
3
1
4
6
mediated protocol of very similar scope. Most of the examples
reported involved unfunctionalized dialkyl and diaryldisulfides.
Here, we report the extension of these operationally facile
radical aromatic thiolation methods to include the synthesis of
(
residues with the trifluoromethylsulfanyl substituents are
manifold (Scheme 1): i) substitution of electron-rich arenes
7
8
9
(
ArH, ArM, M=Mg, B ) with electrophilic SCF
3
reagents; ii)
1
0d-f
trifluoromethylsulfanyl benzenes (Scheme 2, bottom).
Both,
metal-mediated trifluoromethylsulfanylation of electrophilic aryl
dark reactions in the presence of weak base and photoredox
catalytic conditions were studied.
halides and arenediazonium salts with formally anionic SCF
3
1
0
species such as AgSCF
3
or Me
4
NSCF
3
,
iii) reaction of aryl-S
1
1
precursors with trifluoromethylation reagents;
fluorine exchange of polyhalogenoalkyl thioethers. Electrophilic
SCF -containing reagents include the easy-to-handle trifluoro-
methanesulfenyl trifluoroacetate, the disulfide (CF S) the
iv) halogen-
12
3
3
2
,
gaseous ClSCF
reagents comprising the SCF
3
, PhN(Me)SCF
3
, and hypervalent aryliodane
group. Copper, silver, and
3
[
[
a]
b]
D. Koziakov, Dr. M. Majek, Prof. Dr. A. Jacobi von Wangelin
Institute of Organic Chemistry, University of Regensburg, Germany
Prof. Dr. A. Jacobi von Wangelin
Department of Chemistry, University of Hamburg
Martin Luther King Platz 6, 20146 Hamburg, Germany
E-mail: axel.jacobi@chemie.uni-hamburg.de
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Scheme 2. Radical thiolations by photoredox catalysis and base mediation.
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European Journal of Organic Chemistry
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COMMUNICATION
a
Table 1. Base-mediated and photoredox-catalyzed trifluoromethylthiolation.
Results and Discussion
Bis(trifluoromethyl) disulfide,
3 3
F CS-SCF , is a commercial
reagent that can also be freshly prepared on lab scale by a
literature procedure. The synthesis involves three sequential
halogenation steps starting from carbon disulfide (Scheme 3).
However, the low boiling points and toxicity of the intermediates
and the product (~34 °C) require special precautions. Trichloro-
b
Entry
Procedure
Base (equiv.)
Photocatalyst (mol%)
Yield in %
methylsulfenyl chloride was synthesized by chlorination of CS
2
c
1
-
-
-
0
1
5
with elemental chlorine.
The major side reaction is the
c
decomposition of sulfur dichloride to disulfur dichloride which
2
A
B
B
C
C
C
NaOAc (1)
-
40
0
1
6
can be suppressed by the addition of acetylacetone. Halogen
exchange with aqueous HBr afforded trichloromethylsulfenyl
bromide which underwent fluorination and dimerization by action
c
3
-
-
-
-
-
Eosin Y (2)
Eosin Y (2)
4
66
0
1
7
of KF in hot sulfolane. Pure 1,2-bis(trifluoromethyl) disulfide
could be stored in a freezer over longer periods of time without
c
5
[Ru(bpy)
[Ru(bpy)
[Ru(bpy)
3
3
3
]Cl
]Cl
]Cl
2
2
2
(0.5)
(0.5)
(0.5)
1
9
3
decomposition ( F NMR, 282 MHz, CDCl : 45.8 ppm). Our
6
69
59
attempt to replace sulfolane with DMSO as the reaction solvent
in the final step led to rapid decomposition and gas evolution
even below 150 °C.
d
7
[
a] Conditions: 4-Bromobenzenediazonium tetrafluoroborate (0.3 mmol),
DMSO (1.5 mL), under N , 6 h. Procedure A: NaOAc (0.3 mmol), 20 °C; B:
eosin Y (0.012 mmol), irradiation with green LED (525 nm, 3.8 W), 20 °C; C:
Ru(bpy) ]Cl ·6H O (0.012 mmol, bpy=2,2’-bipyridine), irradiation with blue
LED (450 nm, 3.8 W), 20 °C. [b] GC yields vs. internal 1-dodecanenitrile. [c]
dark reaction. [d] 0.5 equiv. (F CS)
2
[
3
2
2
3
2
.
Scheme 3. Synthesis of 1,2-bis(trifluoromethyl) disulfide.
C: [Ru(bpy) ]Cl2
3
6
0
B: Eosin Y
Initial optimization experiments (Table 1) were performed with
equimolar 4-bromobenzenediazonium tetrafluoroborate and
Yield
%]
3 2
(F CS) . The dark reactions in the absence of base gave no
[
A: NaOAc
conversion (entries 1, 3, 5). With sodium acetate (NaOAc) as
weak base, moderate conversion to 4-bromotrifluoromethyl-
sulfanyl benzene was observed (procedure A, entry 2).
Significantly higher yields were obtained from photoredox-
catalytic reactions with eosin Y (B: 2 mol%, 525 nm) and
3
0
[
Ru(bpy)
LED (3.8 W) irradiation (entries 4, 6). Employment of 0.5 equiv.
CS) resulted in slightly lower yields (entry 7). A reaction
3 2 2
]Cl *6H O (C: 0.5 mol%, 450 nm), respectively, under
0
(
F
3
2
0
10
20
t [h]
profile analysis documented the rapid onset of trifluoro-
methylthiolation for all three procedures (>90% relative product
formation within the first 3 h) and the highest reaction rate of the
Figure 1. Reaction profiles of procedures A-C (for conditions, see Table 1).
3 2
photoredox catalysis with only 0.5 mol% [Ru(bpy) ]Cl (Figure 1).
13,14
Based on recent reports,
we postulate a radical mechanism
Then, we subjected a set of five arenediazonium salts to a
comparative study of trifluoromethylthiolation under the three
reaction conditions A-C (Table 2). In all cases, the majority of
product formation occurred in the first 3 h of the reaction.
that is initiated by the reductive activation of the arenediazonium
salt (Scheme 5). With the weak base sodium acetate, this most
likely involves the formation of the diazoacetate adduct which
thermally releases the aryl radical Ar•. Under photocatalytic
conditions, single electron transfer (SET) occurs with the excited
3 2 2
Photoredox catalysis conditions with [Ru(bpy) ]Cl ·6H O fared
best for all substrates tested; eosin Y was only slightly less
active. While being the operationally most simple strategy, the
weak base mediated procedure gave significantly lower yields.
The optimized conditions were then applied to eight different
photocatalyst PC (eosin Y or [Ru(bpy)
reaction with the non-bonding electron donor (SCF
of the resultant disulfide radical generates the trifluoromethylthiyl
radical F CS• which readily engages in hydrogen atom transfer
or possibly recombines with suitable nucleophiles (not detected).
Back-electron transfer (formally from the elusive [NuSCF ] )
3
could be a potential pathway of photocatalyst regeneration.
Upon addition of TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)-oxyl,
3
]Cl
2
). Ar• undergoes rapid
3 2
)
. Cleavage
3
3 2
arenediazonium salts in the presence of [Ru(bpy) ]Cl under
•
irradiation with blue light (450 nm, one external 3.8 W LED per
reaction). Moderate to good yields of the desired aryl trifluoro-
methylsulfides were isolated after only 1 h reaction (Scheme 4).
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European Journal of Organic Chemistry
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COMMUNICATION
a
Table 2. Comparison of procedures A-C for selected arenediazonium salts.
Conclusions
We have developed three related synthetic protocols that enable
the straight-forward trifluoromethylthiolation of readily available
arenediazonium salts with the commercial disulfide (F CS) .
3 2
Weak base-mediated reactions in the presence of one equiv.
NaOAc are operationally most simple but afforded only
moderate yields. The photoredox-catalyzed protocols gave
Entry
1
Ar-SCF
3
A (NaOAc)
B (eosin Y)
Yield in %
3 h (24 h)
3 2
C (Ru(bpy) Cl )
b
b
b
Yield in %
h (24 h)
Yield in %
3 h (24 h)
3
3
significantly higher yields of the Ar-SCF products. With only 0.5
mol% [Ru(bpy) ]Cl ·6H O, very good yields were obtained after
3
2
2
4-Br
35 (40)
30 (33)
75 (76)
28 (34)
27 (31)
27 (33)
55 (66)
50 (56)
77 (77)
53 (67)
73 (81)
59 (60)
67 (68)
57 (59)
77 (79)
61 (71)
89 (89)
68 (69)
irradiation with blue light at room temperature for 1 h.
c
2
4-Br
3
4
5
6
4-OMe
Experimental Section
4-NO
2
Synthesis of arenediazonium salts: The parent aniline (30 mmol) was
dissolved in 32% aqueous HBF
4
(12 mL) at room temperature. An
4-F
aqueous solution of NaNO (30 mmol) in water (4 mL) was added
2
Ph
dropwise at 0 °C over 5 min. The resulting mixture was stirred for 40 min
and the precipitate was collected by filtration and re-dissolved in a
minimal amount of acetone. Diethyl ether was added to precipitate the
diazonium tetrafluoroborate, which was filtered, washed several times
with diethyl ether and dried.
[
a] Conditions: Arenediazonium tetrafluoroborate (0.3 mmol), DMSO (1.5 mL),
under N
2
, 24 h. Procedure A: NaOAc (0.3 mmol), 20 °C.; B: eosin Y (0.006
]Cl ·6H O (0.0015
mmol), blue LED (450 nm, 3.8 W), 20 °C. [b] GC yields vs. internal 1-dode-
canenitrile. [c] 0.5 equiv. (F CS)
mmol), green LED (525 nm, 3.8 W), 20 °C; C: [Ru(bpy)
3
2
2
3
2
.
Base-induced trifluoromethylthiolation: A vial (5 mL) was charged with a
magnetic stir bar, the arenediazonium salt (0.9 mmol), 1,2-bis(trifluoro-
methyl)disulfane (0.9 mmol) and sodium acetate (0.9 mmol) and capped
2
with a rubber septum. The vial was purged with N (5 min), and dry
DMSO (4.5 mL) was added. After 8 h of stirring at room temperature,
water (5 mL) was added to give an emulsion which was extracted with
diethylether (35 mL). The organic phases were washed with brine (5
4
mL) and dried over MgSO . Solvents were evaporated in vacuo, and the
residue was purified by flash column chromatography (SiO
ethyl acetate from 5/0 to 5/1).
2
, pentane/
Photo-catalytic trifluoromethylthiolation: A vial (5 mL) was charged with a
magnetic stir bar, the arenediazonium salt (0.9 mmol) and photocatalyst
(
[
0.018 mmol,
Ru(bpy) ]Cl ∙6H
purged with N (5 min). 1,2-Bis(trifluoromethyl)disulfane (0.9 mmol) was
2
mol% Eosin
Y
or 0.0045 mmol, 0.5 mol%
3
2
2
O). Dry DMSO (4.5 mL) was added, and the vial was
2
added, and the reaction vessel was sealed with a rubber septum. The
mixture was irradiated with green light (eosin Y, LED, 525 nm, 3.8 W) for
6
3 2 2
h or with blue light ([Ru(bpy) ]Cl ∙6H O, LED, 450 nm, 3.8 W) for 1 h.
After the irradiation was discontinued, water (5 mL) was added to give an
emulsion which was extracted with diethylether (35 mL). The organic
Scheme 4. Ru-catalyzed photoredox-trifluoromethylthiolation (isolated yields).
phases were washed with brine (5 mL) and dried over MgSO
were evaporated in vacuo, and the residue was purified by flash column
chromatography (SiO , pentane/ethyl acetate from 5/0 to 5/1).
4
. Solvents
both radical intermediates as TEMPO adducts were observed by
mass spectrometry.
2
(
4-Methoxyphenyl)(trifluoromethyl)sulfane: Colourless oil. Yield: 70%.
1
H-NMR (400 MHz, CDCl
3
): δ, ppm: 7.57 (d, 8.8 Hz, 2H), 6.93 (d, 8.9 Hz,
H), 3.84 (s, 3H). C-NMR (101 MHz, CDCl ): δ, ppm: 161.9, 138.3,
34.8, 129.6 (q, 308 Hz), 115.0, 55.4. F-NMR (282 MHz, CDCl ): δ,
13
2
1
3
19
3
+
ppm: -44.43. LRMS (EI, 70 eV, m/z): 208 [M ].
Acknowledgements
D.K. and M.M. were fellows of the Fonds der Chemischen
Industrie (FCI) and the Graduate School “Photocatalysis” of the
Deutsche Forschungsgemeinschaft (DFG), respectively.
13,14
Scheme 5. Postulated reaction mechanism.
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European Journal of Organic Chemistry
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COMMUNICATION
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2
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European Journal of Organic Chemistry
10.1002/ejoc.201701339
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
The radical trifluoromethylthiolation of
arenediazonium salts with commercial
Radical thiofluorination
Denis Koziakov, Michal Majek, Axel
Jacobi von Wangelin*
bis(trifluoromethyl)
disulfide
was
studied under base-mediated dark
and photoredox-catalytic conditions.
While the operationally simple base
protocol afforded the sulfides in
moderate yields, photoredox catalysis
Page No. – Page No.
Radical Aromatic
Trifluoromethylthiolation: Photoredox
Catalysis vs. Base Mediation
with only 0.5 mol% [Ru(bpy)
up to 90% yield within 3 h.
3 2
]Cl gave
This article is protected by copyright. All rights reserved.