Direct dehydroxytrifluoromethylthiolation of alcohols using silver(I) trifluoromethanethiolate and tetra-n-butylammonium iodide

Article abstract of DOI:10.1002/anie.201409983

An unprecedented reaction for the direct trifluoromethylthiolation and fluorination of alkyl alcohols using AgSCF₃ and nBu₄NI has been developed. The trifluoromethylthiolated compounds and alkyl fluorides were selectively formed by c

Full text of DOI:10.1002/anie.201409983

Angewandte
Chemie
DOI: 10.1002/anie.201409983
Synthetic Methods
Direct Dehydroxytrifluoromethylthiolation of Alcohols Using Silver(I)
Trifluoromethanethiolate and Tetra-n-butylammonium Iodide**
Jian-Bo Liu, Xiu-Hua Xu, Zeng-Hao Chen, and Feng-Ling Qing*
Abstract: An unprecedented reaction for the direct trifluoro-
methylthiolation and fluorination of alkyl alcohols using
AgSCF3 and nBu4NI has been developed. The trifluoro-
methylthiolated compounds and alkyl fluorides were selec-
tively formed by changing the ratio of AgSCF3/nBu4NI. This
protocol is tolerant of different functional groups and might be
applicable to late-stage trifluoromethylthiolation of alcohols.
T
he development of new fluorination and fluoroalkylation
methods is currently an active area of research[1] because
fluorine-containing compounds are widely used in pharma-
ceuticals, agrochemicals, and materials.[2] However, most of
the synthetic methods are focused on the introduction of
fluorinated groups onto aromatic substrates. In contrast, few
breakthroughs have been made in the methodology for the
preparation of fluorine-containing aliphatic compounds.
Thus, the development of new methods for the introduction
of fluorinated groups into aliphatic molecules, especially from
the simple and easily available materials, is highly desirable.
The trifluoromethanesulfenyl group (CF3S) has attracted
special interest because of its strong electron-withdrawing
power and extremely high lipophilicity.[3] Especially during
the past several years, CF3S chemistry has experienced
a renewal.[4] The development of new trifluoromethylthiolat-
ing agents,[5] as well as new trifluoromethythiolation reac-
tions,[6] have attracted attention. Surprisingly, little attention
was paid to the transformation of alcohols into the corre-
sponding trifluoromethyl sulfides. In 1994, Kolomeitsev and
co-workers developed a two-step procedure for the prepara-
tion of trifluoromethyl sulfides from alcohols via a phosphite
intermediate using the toxic and gaseous reagent CF3SSCF3
(Scheme 1a).[7] Very recently, Rueping and co-workers
reported a direct trifluoromethylthiolation of benzylic and
allylic alcohols with CuSCF3 in the presence of stoichiometric
amounts of BF3·Et2O (Scheme 1b).[8] This method suf-
fers from narrow substrate scope and poor functional-
group tolerance because of the strong acidic conditions. In
Scheme 1. Different strategies for dehydroxytrifluoromethylthiolation.
continuation of our research interest in trifluoromethylthio-
lation,[6b,e,g,n,w,ac] we herein report a new strategy for the direct
dehydroxytrifluoromethylthiolation of alcohols (Scheme 1c).
In this protocol, the readily prepared and stable AgSCF3 is
used as the trifluoromethylthiolating agent and the mild
reagent nBu4NI was chosen for promoting the transforma-
tion.
The idea of this work came from the fact that trifluoro-
methylthiol and the corresponding anion are unstable.[9] It
was reported that there is an equilibrium between trifluoro-
methanethiolate with carbonothioic difluoride and fluoride
anion (Scheme 2a).[10] Normally, the trifluoromethanethiolate
Scheme 2. Our new strategy.
[*] J.-B. Liu, Dr. X.-H. Xu, Dr. Z.-H. Chen, Prof. Dr. F.-L. Qing
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
345 Lingling Lu, Shanghai 200032 (China)
E-mail: flq@mail.sioc.ac.cn
is associated with a metal, such as HgII,[11] AgI,[12] or CuI,[13] to
stabilize the CF3S group. Among these stable sources of
trifluoromethanethiolate, AgSCF3 is readily prepared and
widely used for preparation of other trifluoromethylthiolation
agents (such as CuSCF3[13]) and trifluoromethylthiolation
reactions.[6] We wondered if it was possible to apply this
unique property of trifluoromethanethiolate to develop new
reactions, such as direct dehydroxytrifluoromethylthiolation
of alcohols. The proposed reaction mechanism is shown in
Scheme 2b. The activation of AgSCF3 gives the more active
Prof. Dr. F.-L. Qing
College of Chemistry, Chemical Engineering and Biotechnology
Donghua University, Shanghai, 201620 (China)
[**] This work was supported by the National Natural Science
Foundation of China (21421002, 21332010, 21272036), and the
National Basic Research Program of China (2012CB21600).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201409983.
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trifluoromethanethiolate, which subsequently decomposes
into carbonothioic difluoride and fluoride anion. Then the
alcohol reacts with in situ generated carbonothioic difluoride
to generate the carbonofluoridothioate intermediate, which
subsequently undergoes nucleophilic substitution by
trifluoromethanethiolate to provide the trifluoromethylthio-
lated compound.
In 2000, Adams and Clark reported that treatment of
AgSCF3 with nBu4NI led the formation of active source of
trifluoromethanethiolate.[14] Based on this work, we started to
investigate the dehydroxytrifluoromethylthiolation of alco-
hols with AgSCF3, and 4-phenylbutan-2-ol (1a) was used as
the model substrate. Initially, the solvent and temperature
were screened (Table 1, entries 1–6). Toluene was found
Table 1: Optimization of reaction conditions.
Entry Activator
x
y
Solvent
T [8C]
Yield [%][a]
2a
3a
1
2
3
4
5
6
7
8
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NBr
nBu4NCl
KI
1.5 2.0 toluene
1.5 2.0 toluene
1.5 2.0 toluene
1.5 2.0 toluene
1.5 2.0 CH2ClCH2Cl
1.5 2.0 DMSO
RT
50
80
100
80
80
80
80
80
80
80
80
80
80
80
80
n.d.
trace
6
n.d.
3
29
7
32
trace
trace
n.d.
2
19
35
36
62
48
n.d.
n.d.
n.d.
36
20
15
16
trace
26
36
10
1.5
0
toluene
1.5 1.5 toluene
1.5 3.0 toluene
1.5 4.5 toluene
1.5 6.0 toluene
3.0 9.0 toluene
3.0 9.0 toluene
3.0 9.0 toluene
3.0 9.0 toluene
3.0 3.0 toluene
9
10
11
12
13
14
15
16
n.d.
n.d.
4
nBu4NI
52
[a] Yields determined by 19F NMR spectroscopy using trifluoromethoxy-
benzene as an internal standard.
Scheme 3. Dehydroxytrifluoromethylthiolation of primary alcohols.
Reaction conditions: 1 (0.4 mmol), AgSCF3 (1.2 mmol), nBu4NI
(3.6 mmol), toluene (4.0 mL), 808C, 10 h. Yield is that of the isolated
product. [a] 1208C. [b] Additional KI (2.4 mmol) was added. [c] 508C,
additional KI (2.4 mmol) was added. [d] 1008C, nBu4NI (1.2 mmol).
Fmoc=9-fluorenylmethoxycarbonyl.
better than other solvents and the ideal temperature was 808C
(entry 3). However, the trifluoromethylthiolated product 2a
was produced in low yield and the alkyl fluoride 3a was
formed as the major byproduct. To increase the yield of 2a,
we decided to change the nBu4NI/AgSCF3 ratio. No reaction
occurred in the absence of nBu4NI (entry 7). To our delight,
2a became major when the nBu4NI/AgSCF3 ratio was
changed into 3:1 (entries 8–11). The yield of 2a was further
improved to 62% by increasing both of the amount of
AgSCF3 and nBu4NI (entry 12). The additive nBu4NI was
crucial to the reaction yield. Lower yield was found when
nBu4NBr was added, and 2a was not detected when nBu4NCl
and KI were used as activator (entries 13–15). It was note-
worthy that 3a was formed in 52% yield when using 3.0
equivalents of AgSCF3 and nBu4NI (entry 16).
converted into the corresponding trifluoromethyl sulfides in
moderate to excellent yield (Scheme 3). In general, higher
reaction temperature was needed for long-chain alkyl alco-
hols and higher yields were obtained for benzyl alcohols.
Substrates bearing electron-donating and electron-withdraw-
ing groups, such as methoxy, aryl, carbonyl, cyano, nitro,
bromo, and iodo, proceeded well. Esters, amides, and
a number of heterocycles, such as piperidine (1d), pyrrolidine
(1e), pyridine (1y), quinoline (1z), thiazole (1aa) and
benzo[b]thiophene (1ab), were well tolerated. It is note-
worthy that the dehydroxytrifluoromethylthiolation of Ide-
benone, a drug for the treatment of Alzheimerꢀs disease, was
successful and gave 2 f in 50% yield. The protected l-
homoserine 1g was compatible with the reaction conditions,
With the optimized reaction conditions in hand, we next
investigated the substrate scope. Various primary alcohols,
including alkyl, allyl, propargyl, and benzyl alcohols, were
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thus affording the corresponding trifluoromethyl sulfide 2g in
moderate yield. The intermediate of Rosuvastatin, a member
of the drug class of statins, also could be converted into the
trifluoromethylthiolated product 2ac in 93% yield.
In the case of secondary alcohols, the elimination reaction
easily occurred to produce olefins as the major byproducts.
Thus, the addition of another activator, KI, and higher
reaction temperature were needed to achieve moderate yields
(Scheme 4). Esters, amides, and heterocycles were tolerated
As shown the entry 16 of Table 1, this protocol could also
be used for the direct conversion of the hydroxy group into
fluorine. When the ratio of substrate/AgSCF3/nBu4NI was
1:3:3, both the primary alcohol 1b and secondary alcohol 1aq
were transformed into the corresponding alkyl fluorides in
moderate yields (Scheme 5). This method is a rare example of
using a trifluoromethylthiolating agent for a fluorination
reaction.
To gain insight of the reaction mechanism, a carbono-
fluoridothioate intermediate was prepared (Scheme 6). Treat-
Scheme 5. Dehydroxyfluorination of alkyl alcohols 1b and 1aq. DMA=
dimethylacetamide.
Scheme 6. Investigation of the reaction mechanism.
Scheme 4. Dehydroxytrifluoromethylthiolation of secondary alcohols.
Reaction conditions: 1 (0.4 mmol), AgSCF3 (1.6 mmol), nBu4NI
(4.8 mmol), KI (3.2 mmol), toluene (4.0 mL), 1208C, 10 h. Yield is that
of isolated product.
ment of 1b with AgSCF3 and KI gave the carbonofluorido-
thioate 4 in high yield. The nucleophilic substitution of 4 with
in situ generated trifluoromethanethiolate gave the trifluor-
omethylthiolated product 2b in 96% yield. In the absence of
nucleophiles, the elimination of carbonyl sulfide from 4 gave
the alkyl fluoride 3b in 72% yield.[15] These results proved
that the carbonofluoridothioate intermediate is probably
involved in this protocol (Scheme 2b).
In conclusion, we have designed and accomplished an
unusual reaction process for tunable transformation of
alcohols into either trifluoromethylthiolated products or
alkyl fluorides. The chemoselectivity was controlled only by
changing the amount of the activator used. It is well known
that trifluoromethylthiolate is unstable and decomposes into
carbonothioic difluoride and the fluoride anion. We have
successfully used this reactivity for the direct trifluorome-
thylthiolation of alcohols. This investigation is an excellent
example of the use of a side reaction for the development of
new reactions in organic chemistry. The wide application of
under the reaction conditions. The sterically hindered alco-
hols 1ai and 1aj were also effective, although some starting of
the materials were not converted. Tertiary alcohols were not
suitable substrates for this transformation. To further dem-
onstrate the utility of this method, the dehydroxytrifluoro-
methylthiolation of complex compounds were attempted.
When epiandrosterone (1ao), a steroid hormone with weak
androgenic activity, was submitted to the optimal reaction
conditions the desired product 2ao was obtained in 50% yield
with 16:9 diastereoselectivity. The reaction of galantamine
(1ap), a drug used to treat Alzheimerꢀs disease and dementia,
proceeded well and afforded the trifluoromethylthiolated
product 2ap in 80% yield with 1:1 diastereoselectivity. The
above results show that this protocol might be applicable to
late-stage dehydroxytrifluoromethylthiolation of some
medicinally relevant compounds.
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General procedure for dehydroxytrifluoromethylthiolation: AgSCF3
(250.7 mg, 1.2 mmol, 3.0 equiv) and nBu4NI (1329.7 mg, 3.6 mmol,
9.0 equiv) were combined in a Schlenk tube. The tube was mounted
with a reflux condenser and backfilled with N2 (this process was
repeated three times), then toluene (4.0 mL) and alcohol 1 (0.4 mmol,
1.0 equiv) were added via syringe. The tube was placed into a pre-
heated oil bath at 808C with vigorous stirring. After 10 h, the reaction
mixture was cooled to room temperature and filtered through a plug
of silica (eluted with EtOAc). The filtrate was concentrated, and the
product was purified by column chromatography on silica gel (eluent:
hexane) to give product 2.
Received: October 11, 2014
Revised: November 1, 2014
Published online: && &&, &&&&
Keywords: alcohols · chemoselectivity · fluorine · silver ·
.
synthetic methods
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Synthetic Methods
J.-B. Liu, X.-H. Xu, Z.-H. Chen,
F.-L. Qing*
&&&& — &&&&
Silver bullet: A new strategy has been
developed for the direct trifluoro-
methylthiolation of alkyl alcohols using
AgSCF3 and nBu4NI. This protocol does
not require the activation of alcohols in
advance. A variety of alkyl alcohols bear-
ing different functional groups were
Direct
transformed into the corresponding alkyl
trifluoromethyl sulfides in moderate to
good yields.
Dehydroxytrifluoromethylthiolation of
Alcohols Using Silver(I)
Trifluoromethanethiolate and Tetra-n-
butylammonium Iodide
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These are not the final page numbers!