A mild and fast photocatalytic trifluoromethylation of thiols in batch and continuous-flow

Article abstract of DOI:10.1039/c4sc01982b

S-CF₃ bonds are important structural motifs in various pharmaceutical and agrochemical compounds. However, their preparation remains a major challenge in synthetic organic chemistry. Here, we report the development of a mild and fast photocatalytic trifluoromethylation of thiols. The combination of commercially available Ru(bpy)₃Cl₂, visible light and inexpensive CF₃I gas proved to be an efficient method for the direct trifluoromethylation of thiols. The protocol is demonstrated on a wide range of aromatic, hetero-aromatic and aliphatic substrates in both batch and continuous microflow (32 examples, 52-98% yield). Process intensification through continuous microflow application resulted in a 15-fold increase in production rate (0.25 mmol min^-1) due to improved gas-liquid mass transfer, enhanced irradiation as well as convenient handling of the gaseous CF₃ source. Furthermore, the efficiency of the flow process allowed to reduce the amount of CF₃I (1.1 equivalent) to reach full conversion. This journal is

Full text of DOI:10.1039/c4sc01982b

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A mild and fast photocatalytic trifluoromethylation
of thiols in batch and continuous-flow†
Cite this: DOI: 10.1039/c4sc01982b
a
a
a
b
Natan J. W. Straathof, Bart J. P. Tegelbeckers, Volker Hessel, Xiao Wang*
ac
and Timothy Noel*
¨
3
S–CF bonds are important structural motifs in various pharmaceutical and agrochemical compounds.
However, their preparation remains a major challenge in synthetic organic chemistry. Here, we report
the development of a mild and fast photocatalytic trifluoromethylation of thiols. The combination of
3 2 3
commercially available Ru(bpy) Cl , visible light and inexpensive CF I gas proved to be an efficient
method for the direct trifluoromethylation of thiols. The protocol is demonstrated on a wide range of
aromatic, hetero-aromatic and aliphatic substrates in both batch and continuous microflow (32
examples, 52–98% yield). Process intensification through continuous microflow application resulted in a
Received 3rd July 2014
Accepted 7th August 2014
ꢀ1
15-fold increase in production rate (0.25 mmol min
)
due to improved gas–liquid mass
source. Furthermore,
I (1.1 equivalent) to reach full
transfer, enhanced irradiation as well as convenient handling of the gaseous CF
3
DOI: 10.1039/c4sc01982b
the efficiency of the flow process allowed to reduce the amount of CF
3
www.rsc.org/chemicalscience
conversion.
Introduction
The development of mild methods regarding the incorpora-
tion of uorine-containing functional groups has gained
1
increasing attention. This is undoubtedly driven by the
growing demand in the pharmaceutical and agrochemical
industry, as well as its increasing need for the development of
1
8
F-labeled organic compounds for positron emission tomog-
2
raphy (PET) imaging. In particular, the incorporation of
triuoromethyl moieties (CF ) has been widely investigated on
e.g. alkenes, arenes and hetero-arenes. In contrast, the
3
3
4
triuoromethylation of thiols (S–CF ) is much less developed.
3
The incorporation of a triuoromethylthio (S–CF ) motif in a
3
drug molecule results in an extremely high lipophilicity
(
Hansch parameter, p
R
¼ 1.44) and improves the stability of
the molecule in acidic media. Access to such compounds is
crucial since they constitute a key intermediate for the
synthesis of biologically active (triuoromethyl)-sulfoxides
and sulfones.
To date, a number of methods have been developed for the
a
Department of Chemical Engineering and Chemistry, Micro Flow Chemistry & Process construction of S–CF
bonds via direct triuoromethylation of
3
Technology, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven,
5
readily accessible aryl and alkyl thiols. These bonds can be
The Netherlands. E-mail: t.noel@tue.nl; Tel: +31-40-247-3623
b
constructed via an ion-radical mechanism employing inexpen-
Harvard NeuroDiscovery Center, Harvard Medical School and Brigham & Women's
6,7
sive CF3 sources such as CF I or CF Br. However, most of
3
3
Hospital, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA. E-mail:
these methods, if not all, suffer from limited substrate scope,
prolonged reaction times and require harsh conditions, such as
the use of liquid ammonia as a solvent system, elevated pres-
sure and the use of UV light (eqn (1)). A more convenient
xwang21@partners.org
c
Department of Organic Chemistry, Ghent University, Krijgslaan 281 (S4), 9000 Ghent,
Belgium
1
13
19
†
Electronic supplementary information (ESI) available: Detailed H, C and
F
NMR. See DOI: 10.1039/c4sc01982b
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radical-chain approach via a single electron transfer (SET) was aromatic thiols, heteroaromatic thiols and aliphatic thiols were
reported by Koshechko and coworkers but still rendered a very subjected to our optimized triuoromethylation protocol
8
limited scope and relative long reaction times. More recently, (Scheme 1). Aromatic thiols bearing electron-withdrawing and
great effort was conducted in the development of shelf-stable electron-donating functional groups were all competent
+
9
CF
3
-electrophilic (CF
3
1
) reagents, such as Umemoto's reagent
substrates. Notably, most examples could be nished within
0
and Togni's reagent. These reagents are well-known and easy- one hour reaction time (Scheme 1). As expected, aromatic thiols
to-handle triuoromethylating agents and demonstrate good with strong electron-withdrawing functional groups reacted
selectivity and broad substrate scope. However, commercial much slower (up to 5 hours reaction time) but were still
sources of these reagents are expensive, and the preparation obtained in moderate to good yields (Scheme 1, examples 6b,
requires multiple synthetic steps, making them less attractive 8b, 18b). The mildness of our protocol is exemplied by its
11
for scale-up. In contrast, radical CF3 sources, such as CF3I tolerance towards aromatic thiols bearing a free carboxylic acid,
bulk chemical) or triyl chloride (CF SO Cl), would be more an alcohol, or an amine (Scheme 1, examples 9b, 15b, 19b). In
(
3
2
advantageous to use given their low cost price and availability. addition, the presence of chlorine and bromine substituents
In search of a mild and broadly applicable method for the tri- was well tolerated providing opportunities for orthogonal

uoromethylation of thiols, we turned our attention to the use selectivity with cross-coupling chemistry (Scheme 1, examples
12
of visible-light photoredox catalysis. Visible-light photoredox 11b and 12b). These representative examples illustrate the
catalysis has emerged as a mild and efficient method to func- general applicability of our method to prepare S–CF bearing
3
tionalize molecules and is tolerant to a broad range of func- aromatic compounds by photocatalytic triuoromethylation of
tional groups. Recently, we have established the efficient and aromatic thiols.
mild formation of C–S bonds via a photocatalytic Stadler–Zie-
Encouraged by these results, we extended our investigations
13
gler reaction. Hereby, aryl radicals are generated from in situ towards the photocatalytic triuoromethylation of heteroaromatic
prepared diazonium salts which subsequently react with thiols thiols (Scheme 1, examples 20–26b). 2-Mercaptopyridine,
14
to generate the required C–S linkage (eqn (2)). We anticipated 4-mercaptopyridine, 2-mercaptobenzoxazole, 2-mercaptobenzo-
that similar strategy could be exploited for the tri- thiazole, unprotected and protected 2-mercaptobenzimidazole
uoromethylation of thiols, thereby rendering a more general and 2-mercaptopyrimidine could be efficiently triuoro-
and practical approach to the formation of RS–CF compounds methylated within one hour reaction time under the given
a

3
(
eqn (3)). Furthermore, the use of CF I, as an inexpensive, stable conditions. It should be noted that extended reaction times
3
and widely available CF source, makes our method cost-effi- resulted in lower selectivity for the desired compound through
3
1
5
cient. Taking advantage of continuous-ow photochemistry, the incorporation of additional CF
3
-groups on the aromatic
19
we were able to accelerate the developed S–CF
signicantly to increase its throughput and scalability.
3
protocol ring. Aliphatic thiols proved to be the most challenging
16
substrate class (Scheme 1, examples 27–29b). Under the
established reaction conditions, the formation of the
corresponding disuldes could not be prevented. This could be
partially overcome by an in situ reduction of the formed
Results and discussion
20
The proposed triuoromethylation strategy was rst evaluated disulde by adding triphenylphosphine and water.
with thiophenol, Ru(bpy) Cl , and a 24 W uorescent lamp
During the course of our investigations, we observed that
I and CF SO Cl were used as a CF
source the rate of the reaction in batch is affected by the mixing
Table 1, entries 1–3). In the absence of any additive, only a trace efficiency. To establish a better contact between gaseous CF
I was added via
3
2
(
(
Table 1). Both CF
3
3
2
3
3
I
amount of the desired compound (1b) could be observed, while and the liquid reaction mixture in batch, CF
3
the major reaction was the formation of diphenyl disulde (1c). syringe pump and bubbled through the reaction mixture in 10
A high selectivity for the disulde product was found when minutes. A further increase in interfacial area between gaseous
CF
3 2 3
SO
Cl was used, which also occurred in the absence of a CF I and liquid reaction mixture can be obtained in contin-
21
photocatalyst. The use of an organic base effectively suppressed uous-ow microreactors. In such devices, gas–liquid ow
17
by-product formation (Table 1, entries 4–8). Optimal condi- results in the formation of a segmented ow regime which
tions were obtained when 2.0 equivalents of triethylamine (TEA) provides an intense contact between liquid and gas phase.
was introduced to the reaction, resulting in the selective tri- Furthermore, process intensication of photochemical trans-
16,22

uoromethylation of thiophenol within one hour. Further, only formations can be efficiently achieved in microreactors.
The
a slight excess (1.1 equiv.) of TEA was required to obtain full observed intensication is a consequence of the improved
conversion of thiophenol (Table 1, entries 9–10). Control irradiation of the reaction medium in such conned reactors,
experiments established the necessity of both the photoredox which leads to a more uniform local volumetric rate of energy
23
catalyst and the presence of visible light (Table 1, entries 11–12), absorption. The microow setup consists of a high purity
as a high degree of disulde formation or no reaction was peruoroalkoxyalkane (PFA) capillary microreactor (500 mm ID,
observed in both these cases. The formation of the SCF
3
-
2.5 m length, 500 mL volume) and a Tefzel cross-mixer, which
I gas cylinder and two syringes con-
taining the liquid reagents (Fig. 1). CF I was dosed into the
product in the absence of a photocatalyst occurs through was connected to a CF
3
18
homolysis of CF I upon irradiation.
3
3
With the optimized conditions in hand, we set out to explore reactor system by means of a mass ow controller (MFC). The
the scope of this photocatalytic transformation. A broad array of liquid reagents were added by syringe pump and upon
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Table 1 Optimization of reaction conditions
CF
3
I
3 2
CF SO Cl
a
b
b
b
b
Entry
Catalyst
Additive (equiv.)
Conv. (%)
Yield [1b : 1c] (%)
Conv. (%)
Yield [1b : 1c] (%)
1
2
3
4
5
6
7
8
9
Ru(bpy)
Ir(ppy)
Ir(F-ppy)
3
Cl
2
—
—
—
Py (2)
TEA (2)
DIPEA (2)
DBU (2)
TMEDA (2)
TEA (1.1)
TEA (0.5)
TEA (1)
TEA (1)
35
22
26
72
100
100
100
100
100
76
Trace : 33
Trace : 21
Trace : 25
4 : 68
97 : 3
99 : 1
100 : 0
99 : 1
100 : 0
75 : 1
55 : 45
0 : 0
98
100
100
—
—
—
—
—
—
—
0 : 98
0 : 89
5 : 75
—
—
—
—
—
—
—
3
3
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
none
3
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
3
3
3
3
3
3
10
11
12
c
100
0
—
—
—
—
d
Ru(bpy)
3
Cl
2
a
3 3 2
Reaction conditions: thiophenol (1 mmol), CF I (4 mmol) or CF SO Cl (1.2 mmol), photoredox catalyst (1 mol%), MeCN (5 mL), CFL (24 W), room
19 c
b
temperature, 1 hour. Conversion and yield of 1b and 1c are determined by GC and F-NMR. Absence of photocatalyst showed rapid disulde
formation. Reaction carried out in the dark. Abbreviations: bpy: bipyridine, ppy: phenylpyridine, F-ppy: 3,5-diuorophenylpyridine, Py: pyridine,
d
e
TEA: triethylamine, DIPEA: (diisopropyl)ethylamine, DBU: 1,8-diazobicyclo[5.4.0]undec-7-ene, TMEDA: tetramethylethane-1,2-diamine.
Scheme 1 Substrate scope for photocatalytic direct trifluoromethylation. [Section A] Aryl thiols (compounds 1b–19b), [Section B] heteroaryl
thiols (compounds 20b–26b) and [Section C] aliphatic thiols (27b–29b). [a] Batch protocol: thiol (1 mmol), Ru(bpy) Cl (0.01 mmol), CF I (4
3 2 3
mmol) in MeCN (5 mL). Then add TEA (1.1 mmol) and irradiate with a 24 W CFL household light bulb at room temperature. Reported yields are
those of isolated compounds or calculated with 19F-NMR with internal standard for volatile compounds. See ESI† for more details. [b] Flow
protocol: thiol (1 mmol), Ru(bpy)
Cl
3 2
(0.01 mmol), CF
3
I (1.1 mmol), TEA (1.1 mmol) in MeCN are mixed via a cross-mixer and irradiated with an
array of 3.12 W Blue LED's. [c] Additives Ph
3
P/H O (1 : 1, 1 equiv.) were added.
2
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Fig. 1 Continuous-flow setup for the visible-light photocatalytic tri-
fluoro-methylation of thiols.
3
merging with gaseous CF I, a segmented gas–liquid ow was
established. The reaction mixture was exposed to blue LED
irradiation which matches the absorption maximum of the
photocatalyst. Nine different thiols, including aryl, heteroaryl
and alkyl thiols, were evaluated in our continuous-ow system
(Scheme 1).
A signicant acceleration could be observed in all cases;
several examples could be completed within one minute resi-
dence time (Scheme 1, examples 1b, 10b, 11b, 14b, 15b, 20b).
Thiophenols bearing electron-withdrawing functional groups
could be accelerated, however, it was difficult to reach complete
conversion within 30 minutes residence time (Scheme 1, Scheme
2
Synthetic applications of the photocatalytic tri-
fluoromethylation protocol. (i) Use of disulfides as a substrate (eqn (4));
ii) formation of sulfoxides via one-pot photocatalytic tri-
fluoromethylation/oxidation sequence (eqn (5a)), and exploitation of
the orthogonal selectivity between photoredox catalysis and cross-
coupling chemistry (eqn (5b)); (iii) photocatalytic perfluoroalkylation of
example 18b). A substantial increase was observed for cyclo-
hexylthiol (Scheme 1, example 28b). Importantly, it should be
(
a
noted that the required amount of CF
3
I gas could be drastically
reduced in ow to 1.1 equivalents (4 equivalents in batch) due to
the improved contact between the gas and liquid reactants in aryl thiols.
the photomicroreactor.
So far, we only used thiols as substrates for the formation of
triuormethylthio compounds. As was demonstrated with
A
plausible mechanism for the photocatalytic tri-
aliphatic thiols, disulde by-products can be in situ reduced by uoromethylation of thiols is depicted in Fig. 2. Reductive
2
+
the triphenylphosphine/water system and allowed to produce quenching of the exited state of Ru(bpy)3 * occurs via a
the desired S–CF products. Utilizing this protocol, disuldes nitrogen base. Replacing the nitrogen base by an inorganic
could be directly used as substrates for the triuoromethylation base, i.e. K HPO , resulted in the exclusive formation of disul-
3
2
4
2
5
protocol (see Scheme 2, eqn (4)).
The products of this photocatalytic triuoromethylation of tion supports the necessity of a reductive quencher to obtain the
de with no S–CF bond formation (see ESI†). This observa-
3
26
+
thiols may serve as useful synthetic intermediates towards desired product. Next, oxidizing the [Ru(bpy) ] species to its
3
15
interesting biologically active compounds. To demonstrate ground state generates an electrophilic CF radical. This CF3
3
this, compound 7b was oxidized to yield the corresponding radical can subsequently react with the thiol substrate to yield
sulfoxide (Scheme 2, eqn (5a)). Furthermore, as demonstrated the desired S–CF product.
3
above, reductive dehalogenation was not observed under the
current reaction conditions. This feature allows to further
decorate the molecule by e.g. cross-coupling chemistry
(Scheme 2, eqn (5b)).
Wenextexaminedthestructuraldiversityoftheperuoroalkyl
halide coupling partner in this photocatalytic protocol. Efficient
coupling could be achieved with ethyl 2-bromo-diuoroacetate,
peruorohexyliodide and peruorobutyliodide as representative
examples (Scheme 2, below). The coupling with ethyl 2-bromo-
diuoroacetate gives rise to a versatile intermediate (30b) which
1
8
can be used to introduce F via a Ag-catalyzed decarboxylative
24
uorination.
The possibility to prepare peruoroalkyl
analogues represents a signicant advantage of our method
compared to the use of peruoroalkyl electrophilic reagents,
which are either expensive, not commercially available, or diffi-
cult to synthesize.
Fig.
2 Proposed mechanism for the photocatalytic tri-
fluoromethylation of thiols.
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Int. Ed., 2014, 53, 1650–1653; (b) F. Hu, X. Shao, D. Zhu,
L. Lu and Q. Shen, Angew. Chem., Int. Ed., 2014, 53, 6105–
6109; (c) S. Alazet, L. Zimmer and T. Billard, Angew. Chem.,
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triuoromethylthiolation: ; (d) A. Tlili and T. Billard,
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Conclusions
In conclusion, we have developed a mild and fast photocatalytic
approach to the direct triuoromethylation of thiols. The
method was shown to have a broad substrate scope allowing for
3
the preparation of aryl, heteroaryl and alkyl S–CF compounds
in good-to-excellent yields. Furthermore, our protocol allows for
variation of the peruoroalkyl halide coupling partner giving
rise to peruoroalkylated thiophenols. Acceleration of the
photocatalytic protocol was achieved in a continuous-ow
photomicroreactor (reaction times can be reduced to the
6 (a) V. N. Boiko, G. M. Shchupak and L. M. Yagupolskii, Zh.
Org. Khim., 1977, 13, 1057–1061; (b) V. N. Boiko,
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3
minute range). Most notably, only a slight excess of CF I (1.1
equivalents) was required in the continuous-ow experiments
due to excellent gas–liquid mass transfer characteristics. Given
the operational simplicity of both batch and ow protocols, we
anticipate that our photocatalytic method for the tri-
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
uoromethylation of thiols will nd broad application in
academia and industry.
Acknowledgements
9
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