A facile and general approach to 3-((trifluoromethyl)thio)-4 H -chromen-4-one

Article abstract of DOI:10.1021/ol502751k

A facile and efficient synthetic strategy to 3-((trifluoromethyl)thio)-4H-chromen-4-one was developed. AgSCF₃ and trichloroisocyanuric acid were employed here to generate active electrophilic trifluoromethylthio species in situ. This reaction could proceed under mild conditions in a short reaction time and be insensitive to air and moisture.

Full text of DOI:10.1021/ol502751k

Letter
pubs.acs.org/OrgLett
A Facile and General Approach to
3‑((Trifluoromethyl)thio)‑4H‑chromen-4-one
Haoyue Xiang and Chunhao Yang*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Shanghai, 201203, China
S
* Supporting Information
ABSTRACT: A facile and efficient synthetic strategy to 3-((trifluoro-
methyl)thio)-4H-chromen-4-one was developed. AgSCF3 and
trichloroisocyanuric acid were employed here to generate active
electrophilic trifluoromethylthio species in situ. This reaction could
proceed under mild conditions in a short reaction time and be
insensitive to air and moisture.
luorinated organic compounds have attracted considerable
Fattention within organic synthesis, because of their desirable
electronegativity, lipophilicity, and metabolic stability proper-
ties.1 Among these fluorine-containing groups, the trifluoro-
methylthio (SCF3) group possesses a higher Hansch parameter
(π = 1.44), while the trifluoromethyl group has a lower Hansch
parameter (π = 0.88).1d,2 Therefore, medicinal chemists often
incorporate the SCF3 group into organic compounds to enhance
their transmembrane permeation, thus enhancing their bioavail-
ability.3 As a consequence, there are many bioactive products
bearing the SCF3 group, such as anticoccidial drug Toltrazuril,4
insecticide Fipronil,5 and hypotensive agent analogues of
Losartan and Nifedipine6 (Figure 1).
for the trifluoromethylthiolation of aryl halides with AgSCF3,
catalyzed by Pd species.10 Afterward, another Ni-catalyzed
trifluoromethylthiolation of aryl halides with Me4NSCF3 was
reported by Vicic et al.11 More recently, Liu et al. discovered a
Cu-catalyzed trifluoromethylthiolation of aryl halides with
diverse directing groups, using AgSCF3 as a nucleophilic SCF3
reagent.12 Additionally, Cu-catalyzed oxidative trifluoromethyl-
thiolations have been developed by Qing13 and Vicic.14 On the
other hand, a series of elegant electrophilic SCF3 reagents were
also disclosed and employed for direct construction of the SCF3
moiety into organic compounds. In 2009, two trifluoromethane-
sulfenamides were reported as effective electrophilic SCF3
sources for the trifluoromethylthiolation of various substrates,
and these reagents could be easily synthesized from CF3TMS,
diethylaminosulfur trifluoride (DAST), and aniline.15 Another
shelf-stable electrophilic SCF3 reagent, N-(trifluoromethylthio)-
phthalimide, the reactivity of which was further well studied by
Rueping et al.,16 was initially developed by Munavalli.17
Following, a Pd-catalyzed trifluoromethylthiolation of aryl C−
H bonds with a similar reagent, N-(trifluoromethylthio)-
butanimide, was published by Shen et al.18 In 2013, Shibata et
al. reported a Cu-catalyzed trifluoromethylthiolation of
enamines, indoles, and β-keto esters with a hypervalent
iodonium ylide reagent.19 Additionally, a novel trifluoromethyl-
thiolated thioperoxy reagent with interesting reactivity was
designed by Shen’s group.20
Figure 1. Bioactive agents containing an SCF3 group.
In most of the cases mentioned above, trifluoromethyl-
thiolation occurs at preformed arenes. As an alternative, a
conceptually novel approach, in which the new heterocyclic cores
are constructed during the trifluoromethylthiolation process, is
high desirable, from the point of view of atom and step economy.
Therefore, the trifluoromethylthiolation−cyclization reactions
were applied recently into constructing various significant SCF3-
contaning heterocycles, on the basis of the previous works.21
These useful strategies provided a novel route to assemble the
As a result, an explosion of research efforts has been triggered
in developing new and efficient methods to introduce the SCF3
group.3,7 Traditional indirect strategies for the introduction of
the SCF3 group need additional steps, including halogen−
fluorine exchange reactions of trihalogenomethyl thioethers8 and
trifluoromethylations of sulfur-containing compounds.9 How-
ever, the direct introduction of the SCF3 group into organic
molecules has been poorly investigated until recently. Thus,
various modern direct trifluoromethylthiolation methods were
developed.7a In 2011, Buchwald et al. reported a general method
Received: September 17, 2014
Published: October 22, 2014
© 2014 American Chemical Society
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Letter
a
SCF3 group into organic molecules. Various important
heterocylces, such as indoles,22 isocoumarins,23 benzofurans,
and benzothiophenes,24 bearing an SCF3 substituent were
synthesized through a Lewis acid mediated electrophilic
cyclization reaction with trifluoromethanesulfanylamide, where-
as the SCF3 reagents used here must be prepared in advance and
additional Lewis acids were needed to promote these trans-
formations. Meanwhile, Tan reported a practical and easily
handled method for the generation of the active electrophilic
trifluoromethylthio species in situ from trichloroisocyanuric acid
(TCCA) and AgSCF3.25 Our group has concentrated on
developing novel strategies to construct a variety of bioactive
heterocyclic scaffolds for a long time.26 Chromone and its
derivatives, which are found in many natural products and
pharmaceuticals with a wide range of physiological and biological
activities,27 are greatly versatile building blocks for constructing
various heterocycles.28 Therefore, introduction of the SCF3
group to chromones might be very desirable and result in
further advances in the pharmacological applications. Inspired by
pioneering works, we envisioned that compounds 1 could covert
directly to 3-((trifluoromethyl)thio) chromones under mild
conditions through an electrophilic triflluoromethylthiolation−
cyclization reaction (Scheme 1). Therefore, we herein first
Table 1. Investigation of Reaction Conditions
b
entry
solvent
additive
yield (%)
1
MeCN
DCM
THF
A1
A1
A1
A1
A1
A1
A1
A1
A2
A3
none
A1
A1
A1
n.d.
n.d.
80
2
3
4
DMF
DMSO
MTBE
toulene
THF
57
5
n.d.
n.d.
n.d.
6
7
c
8
78
d
9
THF
n.d.
d
10
11
12
13
14
THF
n.d.
THF
n.r.
e
THF
n.d.
Scheme 1. Construction of 3-SCF3-Chromones
f
THF
90
g
THF
87
a
Reaction conditions: additive (0.25 mmol) and AgSCF3 (0.5 mmol)
were mixed, THF (2 mL) was added and stirred for 30 min at rt, and
then compound 1i (0.2 mmol) was added and stirred for another 2 h.
b
c
Isolated yield; n.d. = no 2i detected; n.r. = no reaction. The reaction
d
is carried out under an argon atmoshpere. The major product was 6-
bromo-3-chloro-4H-chromen-4-one. TCCA (0.25 mmol), AgSCF3
demonstrated a facile and general synthetic route to 3-
((trifluoromethyl)thio) chromones via in situ generation of
electrophilic trifluoromethanesulfanyl cation from TCCA and
AgSCF3.
e
(0.5 mmol), and compound 1a were mixed in solvent and stirred for 2
h. 0.3 mmol of TCCA and 0.6 mmol of AgSCF3 were used. 0.4 mmol
of TCCA and 0.8 mmol of AgSCF3 were used.
f
g
Initially, we screened parameters to find the optimal
conditions (Table 1). Based on the reaction conditions adopted
by Tan,25 our present study commenced with mixing the
commercially available TCCA (A1) and AgSCF3 in MeCN. After
the mixture was stirred at rt for 30 min, 1i was added, which was
easily prepared according to literature procedures.29 We
performed a solvent screening at first (Table 1, entries 1−7).
Obviously, the reaction was highly solvent-dependent with good
and moderate yields obtained in THF and DMF respectively
(Table 1, entries 3, 4), while no desired products were detected
in MeCN, DCM, DMSO, MTBE, or toluene (Table 1, entries 1−
2, 5−7). Following, we surveyed the effect of the additive TCCA
on the reaction, revealing that TCCA was indispensable for in
situ generation of the electrophilic SCF3 cation. Subsequently,
we found that a similar yield was obtained when the reaction was
conducted under an argon atmosphere, suggesting that this
reaction was insensitive to air and moisture (Table 1, entry 8).
Other additives A2 and A3 were ineffective in the current
reaction, but with major byproduct of 6-bromo-3-chloro-4H-
chromen-4-one (Table 1, entries 9, 10). And no reaction took
place at all without any additive (Table 1, entry 11). Afterward,
the feeding order of compound 1i was also taken into
consideration. No corresponding product was detected when
compound 1i was added along with TCCA and AgSCF3 at the
beginning of the reaction (Table 1, entry 12). Finally, we
increased the amount of TCCA and AgSCF3 to 1.5 and 3.0 equiv,
respectively, and the yield of the reaction increased into 90%
(Table 1, entry 13). And the yield of the desired product has not
been improved any more when we further increased the amount
of TCCA and AgSCF3 (Table 1, entry 14).
To study the scope and limitations of this approach, various
(E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-ones
1 were prepared and reacted under optimized reaction
conditions (AgSCF3 (0.6 mmol) and TCCA (0.3 mmol) in
THF (2 mL) at rt for 30 min, then compounds 1 were added and
stirred for another 2 h). The results are shown in Scheme 2.
Generally, with both electron-donating and -withdrawing
substituents on the benzene rings, the reaction proceeded
smoothly and provided the corresponding products 2a−2w in
moderate to excellent yields. Simple alkyl, halo, and methoxy
groups substituted at the para-position of the phenol groups of
compound 1 all gave the corresponding 3-((trifluoromethyl)-
thio)chromones 2a−2i in excellent yields. We were pleased to
find that the nitro-substituted compound 1j was a suitable
reactant as well under the standard conditions, leading to the
desired product 2j in 52% yield. The reactants 1 possessing
electron-donating substituents at the meta-position of the phenol
groups gave the desired products in better yields than those with
electron-withdrawing substituents (Scheme 2, 2k−l vs 2m−n). It
was also found that bearing substituents at the meta-position of
the phenol groups of compound 1 gave 3-((trifluoromethyl)-
thio)chromones in lower yields than those at the para-position
for the electron-withdrawing groups (Scheme 2, 2h vs 2n and 2i
vs 2m), while similar yields were achieved for the electron-
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Letter
a
a
,b
Scheme 2. Exploration of Substrate Scope
Scheme 3. Synthetic Utility of This Reaction
a
All of the reactions in eq 2 were not optimized.
Scheme 4. Proposed Mechanism
a
Reaction conditions: TCCA (0.3 mmol) and AgSCF3 (0.6 mmol)
were mixed, THF (2 mL) was added and stirred for 30 min at rt, and
then compound 1 (0.2 mmol) was added and stirred for another 2 h. b
Isolated yield.
donating groups (Scheme 2, 2c vs 2l and 2f vs 2k). Moreover,
compounds 1 with multisubstituents were compatible with the
reaction process as well, providing the corresponding products
2o−2s in good yields. Replacing benzene moieties by
naphthalene moieties for compounds 1 also afforded 3-
((trifluoromethyl)thio)chromone 2t in a good yield. Meanwhile,
aryl-substituted compounds 1u−1w were found to be suitable
substrates. Additionally, the structure of 2a was confirmed by X-
ray crystallographic analysis (Figure 2).30
Subsequently, the enolate intermediate A would further react
with the trifluoromethanesulfanyl cation generated in situ from
TCCA and AgSCF3 to form intermediate B. Finally, N,N-
25
dimethylamine was eliminated from B to provide 3-((trifluoro-
methyl)thio)chromones 2.
In conclusion, we first demonstrated a facile and general
synthetic route to a range of 3-((trifluoromethyl)thio)-
chromones via in situ generation of electrophilic trifluoromethyl-
thio species from trichloroisocyanuric acid (TCCA) and
AgSCF3. This practical and easily handled reaction, which was
insensitive to air and moisture, could occur under mild
conditions in a short reaction time without any extra additive
metal. Moreover, the reaction could be scaled-up easily.
Additionally, the desired 3-((trifluoromethyl)thio)chromones
could covert to diverse (trifluoromethyl)thio-substituted hetero-
cycles. And this method also provides a new direction to optimize
natural bioactive products.
Figure 2. X-ray crystal structure of 2a.
Notably, the reaction is operationally simple and amenable to
gram-scale synthesis in 85% yield (Scheme 3, eq 1). To
demonstrate the synthetic utility of the desired product, we
treated 3-((trifluoromethyl)thio)chromone 2i with amidines and
guanidine,26b,31 furnishing diverse SCF3-group-containing and
nitrogen-containing heterocycles (Scheme 3, eq 2). Moreover,
this approach could be applied in the construction of
(trifluoromethyl)thio-containing analogue 3e of natural top-
opyrone C (Scheme 3, eq 3), which was isolated from the culture
broth of a fungus and showed significant cytotoxic effects as
topoisomerase I inhibitors.32
ASSOCIATED CONTENT
■
S
* Supporting Information
General experimental information and copies of H and 13C
1
NMR of new compounds are also provided. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
A possible mechanism was proposed in Scheme 4. We
envisioned that an intramolecular Michael addition/cyclization
of compound 1 would happen to produce intermediate A.
*E-mail: chyang@simm.ac.cn.
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Organic Letters
Letter
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This paper is dedicated to Professor Yuyuan Xie on the occasion
of his 90th birthday. This work was financially supported by the
Chinese Academy of Sciences (“Interdisciplinary Cooperation
Team” Program for Science and Technology Innovation), the
National Natural Science Foundation of China (81321092), and
SKLDR/SIMM (SIMM1403ZZ-01).
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