Synthesis of Trifluoromethylated Dithiocarbamates via Photocatalyzed Substitution Reaction: Pentafluoropyridine as Activating Reagent

Article abstract of DOI:10.1002/ejoc.202001572

A method for the synthesis of trifluoromethyl-substituted dithiocarbamates from aldehydes is described. The reaction involves nucleophilic trifluoromethylation, derivatization of the silyloxy-group with pentafluoropyridine, and substitution of the fluorin

Full text of DOI:10.1002/ejoc.202001572

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doi.org/10.1002/ejoc.202001572
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Synthesis of Trifluoromethylated Dithiocarbamates via
Photocatalyzed Substitution Reaction: Pentafluoropyridine
as Activating Reagent
Artem A. Zemtsov,[a] Sergey S. Lunkov,[a, b] Vitalij V. Levin,[a] and Alexander D. Dilman*[a]
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A method for the synthesis of trifluoromethyl-substituted
dithiocarbamates from aldehydes is described. The reaction
involves nucleophilic trifluoromethylation, derivatization of the
silyloxy-group with pentafluoropyridine, and substitution of the
fluorinated pyridinyloxy group by dithiocarbamate anion. The
substitution step is performed in the presence of 12-phenyl-
12H-benzo[b]phenothiazine and copper cyanide under irradi-
ation of 400 nm LED.
Importance of organofluorine compounds in pharmaceutical
and agrochemical areas has stimulated development of
methods for their synthesis.[1] Despite significant advances in
organofluorine chemistry, synthesis of novel structural motifs
based on readily available starting materials constitutes an
important problem.[2] In this regard, sulfur compounds bearing
a
fluorinated fragment have attracted considerable
attention.[2b,3]
Dithiocarbamates have demonstrated diverse biological
Scheme 1. Synthesis of fluorinated thiocarbamates.
activities,[4] and their fluorinated derivatives could be interesting
for medicinal studies. We have previously described direct
introduction of a fluorinated dithiocarbamate moiety by using
the conventional carbonyl addition reaction[5] (Scheme 1). Here-
in we report that alcohols 1, which are readily accessed using
the nucleophilic trifluoromethylation chemistry,[6] can be con-
verted into dithiocarbamates 2 using light mediated radical
process.
Compound 3a was selected as a model substrate, and it
was obtained from alcohol 1a by heating with pentafluoropyr-
°
idine and triethylamine at 100 C for 7 hours (Scheme 2,
equation a). However, harsh conditions required for the deriva-
tization of alcohol 1a prompted us to develop a milder
protocol. It is known that alcohols 1 are routinely obtained from
aldehydes and the Ruppert–Prakash reagent (Me3SiCF3) medi-
ated by fluoride ion.[6] We proposed that silyl ethers, which are
the primary products of nucleophilic trifluoromethylation, can
be directly converted into Pyf-derivatives 3 by interaction with
pentafluoropyridine. Thus, benzaldehyde was reacted with the
Ruppert–Prakash reagent in the presence of cesium fluoride
(5 mol%) in tetrahydrofuran for one hour. Then, pentafluoropyr-
idine and substoichiometric amount of triethylamine (20 mol%)
were added, and after overnight stirring, ether 3a was cleanly
formed (equation b). Though it can be isolated in 95% yield,
the crude product obtained after simple aqueous work-up is of
sufficient purity, and this material can be used further without
purification. The formation of 3a is mediated by cesium
fluoride, which is present from the trifluoromethylation step,
and involves generation of the alkoxide anion followed by
aromatic nucleophilic substitution of fluoride.
Typically, reactions involving homolytic cleavage of the CÀ O
bond proceed via preliminary derivatization into xanthates[7] or
oxalates[8] with the resulting carbon-centered radicals either
abstracting a hydrogen atom or being trapped by π-systems.[9,10]
Recently, perfluorinated pyridine was used as an activating
reagent for the cleavage of CÀ S[11] and NÀ O bonds[12] under
photocatalytic conditions. In this work we demonstrate that
2,3,5,6-tetrafluoropyridinyl (Pyf) ethers 3 derived from alcohols
1 can undergo light mediated substitution reaction by the
dithiocarbamate anion.
[a] Dr. A. A. Zemtsov, S. S. Lunkov, Dr. V. V. Levin, Dr. A. D. Dilman
N. D. Zelinsky Institute of Organic Chemistry
Leninsky prosp. 47, 119991 Moscow, Russian Federation
E-mail: adil25@mail.ru
Reaction of tetrafluoropyridinyl ether 3a with potassium
pyrrolidine-derived dithiocarbamate was evaluated under pho-
tocatalytic conditions (Table 1). Among various photocatalysts,
12-phenyl-12H-benzo[b]phenothiazine[13] (3 mol%) irradiated
with 400 nm LED provided the best results. Copper additives
[b] S. S. Lunkov
Moscow State University, Department of Chemistry
Leninskie Gory 1–3, 119991 Moscow, Russian Federation
Supporting information for this article is available on the WWW under
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with good solubility of potassium dithiocarbamate and its
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generated copper salts. Acetic acid as additive exhibited a
beneficial effect, presumably, due to its ability to decrease the
nucleophilicity of the dithiocarbamate anion. Indeed, it was
shown by a blank experiment that in the presence of the
dithiocarbamate salt, a slow nucleophilic substitution of fluoride
in the pyridine ring of staring substrate 3a occurs. Without the
photocatalyst, trace amounts of the product were formed, but
without light the reaction did not proceed at all (entries 4 and
5). In 19F NMR spectra of the reaction mixtures, a set of signals
of tetrafluorinated pyridine fragment is observed, which is
ascribed to fluorinated 4-hydroxypyridine (PyfOH) or its anion.
Under the optimized conditions, a series of aldehydes were
converted to dithiocarbamates 2 (Table 2). The reaction works
with aldehydes bearing electron donating and electron with-
drawing groups. Unfortunately, the reaction was unsuccessful
with hydrocinnamic aldehyde and acetophenone, since in these
cases photocatalytic substitution was problematic with low
conversions being observed. With cinnamic aldehyde, the
corresponding allylic ether 3 was formed, but its radical reaction
gave a complex mixture.
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The proposed mechanism is shown in Scheme 3. The light
activated catalyst reduces substrate 3 to generate radical anion,
which eliminates the stabilized alkoxide anion to give the CF3-
substituted benzyl radical.[15] The radical is trapped by a copper
species formed between copper cyanide and dithiocarbamate
anion, and the copper(II) intermediate is oxidized by cationic
Scheme 2. Synthesis of compound 3a.
Table 1. Optimization studies.
Table 2. Synthesis of dithiocarbamates 3 from aldehydes.[a]
#
Deviation from standard conditions
Y. of 2a [%][a]
1
2
none
no AcOH
80
73
3
4
no CuCN
no photocatalyst
33[b]
<5[c]
–
5
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no light
Ir(ppy)3 (0.25%) instead of 4
[Ir(dtbbpy)(ppy)2]PF6 (0.25%) instead of 4
4CzIPN (1%) instead of 4
3DPA2FBN (1%) instead of 4
CH3CN instead of DMSO
CH2Cl2 instead of DMSO
55[b]
15[b]
9[b]
–
23[b]
20[b]
[a] Isolated yield. [b] Determined by 19F NMR with PhCF3 as internal
standard. [c] According to GC-MS analysis.
are frequently used to mediate formation of carbon-heteroatom
bonds via reductive elimination of Cu(III) species.[14] Here, the
presence of copper cyanide was important to achieve high
product yield of 80%, as without the copper salt the yield
dropped to 33% with significant amounts of by-products
arising from dimerization of the 1-phenyl-2,2,2-trifluoroethyl
radical being detected by GC-MS analysis (entry 3). DMSO also
turned out to be the best solvent, which may be associated
[a] Yield of 2 calculated on the corresponding aldehyde.
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Scheme 5. Synthesis of thiols 5. [a] Determined by 19F NMR with PhCF3 as
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internal standard.
treatment of compounds 2 with lithium aluminum hydride in
refluxing ether effects the desired transformation (Scheme 5).
Thiols 5a,h were formed in reasonable yields, though high
volatility of thiol 5a led to decreased yield upon isolation.
In summary, a method for the synthesis of trifluorometh-
ylated dithiocarbamates from aldehydes is described. The
reaction involves intermediate formation of tetarfluoropyridinyl
ethers, which undergo photocatalytic substitution of the
pyridinyloxy-group by dithiocarbamate anion. In the dithiocar-
bamate products, the carbamoyl group can be removed
affording trifluoromethylated thiols.
Scheme 3. Proposed mechanism.
form of the photocatalyst leading to a copper(III) species with
subsequent reductive elimination.
To support the radical character of the substitution reaction,
several experiments were performed (Scheme 4). Thus, the
desired reaction of ether 3a with potassium dithiocarbamate
was completely inhibited by TEMPO (2 equiv). When ether 3a
was irradiated in the presence of a nitrone, nitroxyl radical 6
was detected by EPR spectroscopy.
Compounds 2 can be considered as precursors of fluori- Experimental Section
nated thiols, if it would be possible to remove the thiocarba-
moyl group. It should be noted that methods for the synthesis
of the CF3-susbtituted thiols are rare.[16] Indeed, it was shown in
the literature that a conventional oxygen/sulfur exchange using
Lowesson reagent, which could be anticipated to convert
alcohols 1 to the corresponding thiols, is inefficient.[17] Starting
from compounds 2, initial experiments involving base mediated
hydrolytic cleavage of the thiocarbamoyl fragment were
unsuccessful. After considerable experimentation we found that
Synthesis of 2a–q (General Procedure 1).
Aldehyde (0.5 mmol) was added to a stirred suspension of dry
cesium fluoride (4 mg, 0.025 mmol) in THF (1 mL). The reaction
vessel was immersed in a water bath and then (trifluoromethyl)
trimethylsilane (89 μL, 0.6 mmol) was added dropwise. The reaction
was stirred for 1 hour at room temperature, then NEt3 (14 μL,
0.1 mmol) and pentafluoropyridine (82 μL, 0.75 mmol) were added.
The resulting mixture was stirred overnight at room temperature,
diluted with water (5 mL) and extracted with methyl tert-butyl ether
(3×3 mL). The combined organic layers were dried over Na2SO4 and
concentrated under the pressure of 400 Torr. The residue was
dissolved in a small amount of methyl tert-butyl ether, transferred
into a tube, and the solvent was evaporated under vacuum, and
dissolved in DMSO (1 mL). Then, CuCN (5 mg, 0.05 mmol), 12-
phenyl-12H-benzo[b]phenothiazine (4 mg, 0.015 mmol), AcOH
(37 μL, 0.65 mmol) and potassium pyrrolidine-1-carbodithioate
(120 mg, 0.65 mmol) were added successively. The tube was briefly
evacuated (7 Torr), and backfilled with argon. The tube was sealed
with a screw cap, irradiated by 400 nm LED matrix (80 W) for
2 hours with stirring; during irradiation, the tube was cooled with
°
water (18 C). The reaction was quenched with water (5 mL) and
extracted with methyl tert-butyl ether (3×3 mL). The combined
organic phases were filtered through a small pad of Na2SO4,
concentrated under reduced pressure, and the residue was purified
by column chromatography.
Synthesis of 5a, h (General Procedure 2).
A solution of dithiocarbamate 2 (0.3 mmol) in diethyl ether (1.0 mL)
was added dropwise to a stirred suspension of lithium aluminum
hydride (23 mg, 0.6 mmol) in diethyl ether (1.0 mL), and the mixture
Scheme 4. Mechanistic experiments.
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[5] a) A. S. Maslov, V. O. Smirnov, M. I. Struchkova, D. E. Arkhipov, A. D.
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residue purified by flash chromatography in pentane. In case of
thiol 5h, the mixture was extracted with hexane (3×3 mL), the
combined organic phases were concentrated under reduced
pressure, and the residue was purified by column chromatography.
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This work was supported by the Russian Science Foundation
(project 20-13-00112).
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Dithiocarbamates
· Fluorine · Photocatalysis ·
Radical reactions · Trifluoromethylation
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Manuscript received: December 1, 2020
Revised manuscript received: December 24, 2020
Accepted manuscript online: December 29, 2020
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