Silver-catalyzed decarboxylative trifluoromethylthiolation of aliphatic carboxylic acids in aqueous emulsion

Article abstract of DOI:10.1002/anie.201402573

A silver-catalyzed decarboxylative trifluoromethylthiolation of secondary and tertiary carboxylic acids under mild conditions tolerates a wide range of functional groups. The reaction was dramatically accelerated by its performance in an aqueous emulsion, which was formed by the addition of sodium dodecyl sulfate to water. It was proposed that the radical, which was generated from the silver-catalyzed decarboxylation in the "oil-in-water" droplets, could easily react with the trifluoromethylthiolating reagent to form the product.

Full text of DOI:10.1002/anie.201402573

Angewandte
Chemie
DOI: 10.1002/anie.201402573
Trifluoromethylthiolation
Silver-Catalyzed Decarboxylative Trifluoromethylthiolation of
Aliphatic Carboxylic Acids in Aqueous Emulsion**
Feng Hu, Xinxin Shao, Dianhu Zhu, Long Lu, and Qilong Shen*
Abstract: A silver-catalyzed decarboxylative trifluoromethyl-
thiolation of secondary and tertiary carboxylic acids under
mild conditions tolerates a wide range of functional groups.
The reaction was dramatically accelerated by its performance
in an aqueous emulsion, which was formed by the addition of
sodium dodecyl sulfate to water. It was proposed that the
radical, which was generated from the silver-catalyzed decar-
boxylation in the “oil-in-water” droplets, could easily react
with the trifluoromethylthiolating reagent to form the product.
limited.[7,8] Billard and co-workers reported the electrophilic
addition of a trifluoromethylthiolated reagent to olefins in
excellent yields.[5b] Qing and co-workers reported reactions of
allylsilane or tryptamine derivatives with Billardꢀs reagent to
form secondary or tertiary alkyl trifluoromethylthioethers.[5d,f]
The groups of Shen and Shibata independently reported the
trifluoromethylthiolation of b-ketoesters with two different
electrophilic trifluoromethylthiolating reagents.[6a,b,5i] More
recently, the groups of Rueping and Shen reported the
asymmetric trifluoromethylthiolation of b-ketoesters.[5j,6b]
Reactions using Billardꢀs reagent generally required the use
of a strong Lewis or Brønsted acid to activate the CF3S
reagent. Other reactions only proceeded in high yields with a-
substituted b-ketoesters. Thus, the development of new
methods for the direct introduction of the trifluoromethylthio
group at sp3-hybridized secondary or tertiary carbon centers
with broad substrate scope and functional-group tolerance is
highly desirable.
Aliphatic carboxylic acids are air- and water-stable,
readily available, and cheap raw materials that can be easily
converted into derivatives with different functional groups.
One of the fundamental functional-group transformations in
organic chemistry is the decarboxylative halogenation of
carboxylic acids mediated by a silver salt (Hunsdiecker
reaction), which has been well developed since 1930s.[9]
More recently, Hunsdiecker-type reactions using catalytic
amounts of silver salts have also been developed.[10]
As the most electronegative element, fluorine has played
a pivotal role in agrochemistry and pharmaceutical chemistry,
with an increasing number of fluorinated drugs on the market
and drug candidates under development at different stages.[1]
Among the different fluorinated functional groups, the
trifluoromethylthio group (CF3S) is highly valuable because
of its advantageous effects, as the incorporation of the
trifluoromethylthio group often improves the lipophilicity of
a compound and suppresses metabolic detoxification pro-
cesses to increase the in vivo lifetime of a drug.[2] This fact has
stimulated a growing interest in the development of new
reagents and methods for the direct introduction of the
trifluoromethylthio group under mild conditions.[3] For
instance, several electrophilic trifluoromethylthiolating
reagents have been developed, which allow the trifluoro-
methylthiolation of common nucleophiles, such as b-ketoest-
ers, alkynes, aryl or alkyl Grignard reagents, and lithium
reagents.[4,5a–j] In addition, significant advances have been
achieved recently in the transition-metal-mediated tri-
fluoromethylthiolation, with functional groups such as aryl
boronic acids and halides undergoing efficient trifluoro-
methylthiolation under palladium, nickel, or copper cataly-
sis.[5k–p]
Inspired by these advances and considering that the CF3S
group is generally referred to as a pseudohalide, we reasoned
that a Hunsdiecker-type decarboxylative trifluoromethyl-
thiolation (Scheme 1) may be possible if the alkyl radical
generated from the well-known oxidative decarboxylation
could be efficiently trapped by the electrophilic trifluoro-
methylthiolating reagent 1, which we recently developed in
our lab.[6]
Despite these recent great achievements in this area,
methods for the general and site-specific formation of sp3-
À
hybridized secondary or tertiary carbon SCF3 bonds are
[*] Dr. F. Hu,[+] X. Shao,[+] D.-H. Zhu, Prof. Dr. L. Lu, Prof. Dr. Q. Shen
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (China)
Scheme 1. Proposed radical trifluoromethylthiolation.
E-mail: shenql@sioc.ac.cn
[+] These authors contributed equally to this work.
[**] We gratefully acknowledge financial support from the National
Basic Research Program of China (2012CB821600), the Key
Program of the Natural Science Foundation of China (21032006),
the National Natural Science Foundation of China (21172245/2117
and 2244/21372247), and SIOC. We thank Prof. Chaozhong Li for
insightful discussions.
One challenge associated with this approach is the
possible oxidation of the product alkyltrifluoromethyl-
thioether by the oxidant that is used to reoxidize the silver(I)
salt. To facilitate the formation of the alkyltrifluoromethyl-
thioether and minimize the side reaction, we used a biphasic
system that could physically separate the alkyltrifluoro-
methylthioether from the oxidant, as inspired by the emulsion
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402573.
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radical polymerization process.[11] We herein report the use of
an aqueous emulsion, which was formed by the addition of
sodium dodecyl sulfate (SDS) in water and dramatically
accelerated a silver-catalyzed decarboxylative trifluorome-
thylthiolation of secondary and tertiary alkyl carboxylic acids
under mild conditions. Radical-clock and radical-cyclization
experiments suggested that the reaction proceeded through
a free-radical process.
In order to test if the alkyl radical could be trapped by
reagent 1, we initially studied the conversion of 1-adamantane
carboxylic acid to trifluoromethylthiolated adamantine using
reagent 1 in the presence of catalytic amounts of different
silver salts (20 mol%) and 1.0 equivalent of K2S2O8 as the
oxidant in different solvents.[12] As expected, the desired
product was obtained in less than 12% yield when silver salts
such as AgNO3, AgOTf, AgBF4, or AgOAc were used in
different solvents, such as THF, CH3CN, DMF, CH2Cl2, and
acetone, at room temperature or at 508C (results not shown in
the table). Furthermore, no significant improvement was
observed when the reaction was conducted in a solvent
mixture such as CH3CN/H2O (1/1; Table 1, entry 2), acetone/
H2O (1/1), or THF/H2O (1/1). In contrast, the reaction
generated the desired product in 60% yield when it was
conducted in the presence of 1.0 equivalent of sodium
dodecyl sulfate (SDS) in CH3CN/H2O (1/1; Table 1,
entry 4). Decreasing the amount of SDS to 0.2 equivalent
led to a higher yield (84%; Table 1, entry 5). Reactions in the
presence of 0.2 equivalent of SDS conducted in acetone/H2O
(1/1) generated the product in 83% yield, while reactions in
other mixed solvents, such as DMF/H2O, THF/H2O, or
CH2Cl2/H2O, were not effective at all (Table 1, entries 7–9).
Interestingly, a higher percentage of water in the mixed
solvent led to an increased yield of the product (92%; Table 1,
entry 6). When the reaction was conducted in pure water with
0.2 equivalent of SDS, the desired product was generated in
98% yield as determined by 19F NMR spectroscopy with an
internal standard (Table 1, entry 10).[13] The yield decreased
to 81% when 0.1 equivalent of SDS was used (Table 1,
entry 11). The use of other surfactants, such as sodium
methylsulfonate or sodium 4-dodecylbenzenesulfonate,
under otherwise the same conditions resulted in much lower
yields (Table 1, entries 12–14). Likewise, the use of other
silver salts as the catalyst also led to lower yields (Table 1,
entries 15–17). In the absence of the silver salt, no product
was observed (Table 1, entry 18).
With an efficient protocol for the decarboxylative tri-
fluoromethylthiolation in hand, we next investigated its scope
with aliphatic carboxylic acids (Table 2). The reaction con-
ditions were quite general for tertiary and secondary alkyl
carboxylic acids. A wide range of substrates with different
functional groups, such as chloride, bromide, esters, and
electron-rich arenes, underwent the efficient decarboxylative
trifluoromethylthiolation to afford the corresponding prod-
ucts in good to excellent yields (Table 2, 3b–c, 3j, 3q–s). A
cyclopropyl carboxylic acid also underwent the decarboxyla-
tive trifluoromethylthiolation to give the corresponding
product in good yields (Table 2, 3e–f). Notably, no competing
electrophilic trifluoromethylthiolation of electron-rich arenes
was observed (Table 2, 3e–f, 3l, 3s). In addition, the reaction
was compatible with alkene and alkyne groups, thus illustrat-
ing an orthogonal reactivity of the silver-catalyzed decarbox-
ylative trifluoromethylthiolation to classical electrophilic
addition reactions (Table 2, 3k–l). Reactions of primary
alkyl carboxylic acids, however, occurred much slower and
in lower yield than those of tertiary and secondary alkyl
carboxylic acids. The desired products were obtained in only
20–30% yield in a mixture of CH3CN/H2O (Table 2, 3t–u).
The reaction of benzoic acid with reagent 1 under the
optimized conditions did not generate the trifluoromethyl-
thiolated product at all. With regard to a possible scale-up of
the reaction, the yield of 3a dropped slightly to 71% when the
reaction was conducted on a 2.0 mmol scale (Table 2).
Table 1: Optimization of reaction conditions for silver-catalyzed decar-
boxylative trifluoromethylthiolation.[a]
Entry AgX
Additive
Solvent
Yield [%][a]
1
2
3
4
5
6
7
8
AgNO3
AgNO3
AgNO3
–
–
–
CH3CN
CH3CN/H2O
H2O
11
12
<2
60
84
AgNO3 nC12H25SO3Na[c]
AgNO3 nC12H25SO3Na
AgNO3 nC12H25SO3Na
AgNO3 nC12H25SO3Na
AgNO3 nC12H25SO3Na
AgNO3 nC12H25SO3Na
AgNO3 nC12H25SO3Na
AgNO3 nC12H25SO3Na[f]
AgNO3 CH3SO3Na
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O[d] 92
acetone/H2O
DMF/H2O
CH2Cl2/H2O
H2O
H2O
H2O
66
<2
9
<2
10
11
12
13
14
15
16
17
18
98 (91)[e]
In general, silver-mediated oxidative decarboxylative
functionalization was suggested to proceed through a radical
pathway. The reactivity of the carboxylic acids in Table 2
decreases in the order of tertiary, secondary > primary @ aro-
matic, which also indicates that a radical pathway is likely. In
order to gain experimental evidence to support this assertion,
two sets of experiments were conducted. In the first experi-
ment, cyclopropyl carboxylic acid 4 was prepared as a radical
clock and subjected to the reaction conditions. The ring-
opening products were generated in 87% yield as a mixture of
stereoisomers in a ratio of 3:1 [Eq. (1)]. No trifluorome-
thylthiolated cyclopropane derivative was observed by 1H and
19F NMR spectroscopy of the crude reaction mixture.
81
–
70
3
11
71
59
–
AgNO3 4-(nC12H25)C6H4SO3Na H2O
AgNO3 nBu4NHSO4
AgSbF6 nC12H25SO3Na
H2O
H2O
H2O
H2O
H2O
AgOTf
AgOAc nC12H25SO3Na
nC12H25SO3Na
nC12H25SO3Na
–
[a] Reaction conditions: 1-adamantane carboxylic acid (0.3 mmol),
reagent 1 (0.45 mmol), AgX (30 mol%), additive (20 mol%), K2S2O8
(0.3 mmol), solvent (2.0 mL, 1:1 (v/v) for mixed solvent) at 508C for
12 h. [b] Yields were determined by 19F NMR spectroscopy with
1-fluoronaphthalene as the internal standard. [c] 1.0 equiv of SDS was
used. [d] 1:2 (v/v). [e] Yield of isolated product. [f] 10 mol% of SDS was
used.
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Table 2: Scope of silver-catalyzed decarboxylative trifluoromethylthiola-
tion.[a]
gested the involvement of a free-radical mechanism in the
silver-catalyzed decarboxylative trifluoromethylthiolation.
The experiments further suggested that the formation of
primary alkyl radicals from primary alkyl carboxylic acids was
difficult under the current conditions.[10] Once the primary
alkyl radical was formed, it could easily react with reagent 1 to
form the trifluoromethylthioether.
To probe if a free alkyl radical can easily react with
reagent 1 to form alkyl trifluoromethylthioether, we studied
the reaction of alkyl trifluoroborate potassium salts with
reagent 1 in the absence of a silver catalyst, as it is well-known
that alkyl radicals can be easily formed from alkyl trifluoro-
borates in the presence of an oxidant.[14] Reactions of four
different primary alkyl trifluoroborate salts with reagent
1 formed the corresponding alkyl trifluoromethylthioether in
good yields [Eq. (4)]. The reactions occurred in much lower
yields in the absence of SDS. These results supported our
assertion that free primary alkyl radicals can easily react with
reagent 1 to form the products.
To gain some understanding about the effect of the
surfactant on the silver-catalyzed decarboxylative trifluoro-
methylthiolation, we studied the kinetics of the reactions in
[a] Reaction conditions: alkyl carboxylic acid (0.3 mmol), reagent
1 (0.45 mmol), AgNO3 (30 mol%), K2S2O8 (0.3 mmol), SDS (20 mol%),
H2O (2.0 mL) at 508C for 12 h, yields of isolated products are given.
[b] The reaction was conducted in CH3CN/H2O (1:2). [c] 24 h. [d] CH3-
(CH2)11SO3Na (0.3 mmol) was used.
In the second set of experiments, compounds 5a–c were
synthesized and subjected to the silver-catalyzed reactions
with reagent 1 in water to generate the ring-closed trifluoro-
the presence of different amount of SDS by monitoring the
reaction with 19F NMR spectroscopy. A comparison of the
silver-catalyzed reactions of 1-adamantane carboxylic acid
with reagent 1 in the presence of 0, 6, 10 and 20 mol% SDS is
shown in Figure 1. The reaction in the absence of SDS
occurred sluggishly with less than 15% conversion even after
6 hours. In contrast, the reaction occurred much faster in the
presence of SDS. Interestingly, reactions in the presence of
10 mol% SDS or above were significantly faster and occurred
in much higher yields than those using 6 mol% SDS. Notably,
an emulsion was formed for reactions using 10 or 20 mol%
SDS, which indicated the formation of “oil-in-water” drop-
lets[15] (Figure 1, right). The size of the droplets was deter-
methylthiolated spiro products 3w–y in 82%, 75%, and 55%
yield, respectively [Eq. (2),(3)]. We reasoned that the radicals
generated from the silver-mediated oxidative decarboxylation
undergo irreversible intramolecular 5-exo-cyclization at
a much faster rate than those of the bimolecular radical
quenching process. Both sets of experiments strongly sug-
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solvent effects.[13,17] Radical-clock and radical-cyclization
experiments suggested that the reaction proceeded through
a free-radical process. The effect of aqueous emulsions on
other reactions is currently investigated in our laboratory.
Received: February 18, 2014
Published online: && &&, &&&&
Keywords: decarboxylation · fluorine · radicals · silver ·
.
trifluoromethylthiolation
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Figure 1. Left: A comparison of the silver-catalyzed decarboxylative
trifluoromethylthiolation in the presence of 0, 6, 10, and 20 mol% of
SDS. Right: Image of the reaction mixture.
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of SDS and water to form “oil-in-water” droplets. Silver(II)
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Scheme 2. Proposed mechanism.
silver(I) salts with the alkyl carboxylic acids in the presence of
K2S2O8, could penetrate into the droplets. The alkyl radical,
generated from the silver(II) carboxylate through a concerted
decarboxylation pathway,[16] then reacted with reagent 1 to
form the corresponding product and a tertiary alkoxy radical.
The alkoxy radical decomposed to form 1-(2-iodophenyl)-
ethanone. This ketone was isolated in every silver-catalyzed
decarboxylative trifluoromethylthiolation reaction, in agree-
ment with the current mechanistic assumption. On the other
hand, in the water phase, the silver(I) intermediate was easily
reoxidized by K2S2O8 to regenerate the active silver(II)
catalyst.
In summary, we have developed a silver-catalyzed decar-
boxylative trifluoromethylthiolation of secondary and tertiary
alkyl carboxylic acids under mild conditions. The reaction
tolerates a wide range of functional groups. In addition, the
reactions were dramatically accelerated by their performance
in an aqueous emulsion, which was formed by the addition of
sodium dodecyl sulfate (SDS) to water. The use of water as
the solvent for organic reactions is advantageous, as it is
cheap, nontoxic, and nonflammable, and has extraordinary
4
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Chemie
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Trifluoromethylthiolation
F. Hu, X. Shao, D.-H. Zhu, L. Lu,
Q. Shen*
&&&& — &&&&
Silver-Catalyzed Decarboxylative
Trifluoromethylthiolation of Aliphatic
Carboxylic Acids in Aqueous Emulsion
Oil-in-water: Secondary and tertiary car-
boxylic acids were successfully trans-
formed to their trifluoromethylthiolated
derivatives using the title reaction, which
tolerates a wide range of functional
groups. The reaction was dramatically
accelerated by the use of an aqueous
emulsion as the reaction medium, which
was formed by the addition of sodium
dodecyl sulfate (SDS) in water.
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!