2-Position-Selective Trifluoromethylthiolation of Six-Membered Heteroaromatic Compounds

Article abstract of DOI:10.1021/acs.orglett.9b01474

The regioselective C-H trifluoromethylthiolation of six-membered heteroaromatic compounds via nucleophilic attack of a CF₃S source on the electrophilically activated six-membered heteroaromatic ring was developed. The reaction proceeds in good yield with good functional group tolerance, even on a gram-scale. The key to the successful regioselective transformation is the presence of an additive (2,4-dinitrobenzenesulfonyl chloride). The regioselective trifluoromethylthiolation of quinidine derivative is also demonstrated. Trifluoromethylthiolation, followed by S-oxidation, affords the corresponding sulfones.

Full text of DOI:10.1021/acs.orglett.9b01474

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
2‑Position-Selective Trifluoromethylthiolation of Six-Membered
Heteroaromatic Compounds
Ryuhei Muta,‡ Takeru Torigoe,†,‡ and Yoichiro Kuninobu*,†,‡
†Institute for Materials Chemistry and Engineering, Kyushu University, 6-1 Kasugakoen, Kasuga-shi, Fukuoka 816-8580, Japan
‡Department of Molecular and Material Sciences, Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1
Kasugakoen, Kasuga-shi, Fukuoka 816-8580, Japan
S
* Supporting Information
ABSTRACT: The regioselective C−H trifluoromethylthiola-
tion of six-membered heteroaromatic compounds via
nucleophilic attack of a CF3S source on the electrophilically
activated six-membered heteroaromatic ring was developed.
The reaction proceeds in good yield with good functional
group tolerance, even on a gram-scale. The key to the
successful regioselective transformation is the presence of an
additive (2,4-dinitrobenzenesulfonyl chloride). The regioselective trifluoromethylthiolation of quinidine derivative is also
demonstrated. Trifluoromethylthiolation, followed by S-oxidation, affords the corresponding sulfones.
pyridine and quinoline derivatives have been obtained via
he trifluoromethylthio group (SCF3) is an important
Tfunctional group found in many pharmaceuticals and the deprotonation of pyridine and quinoline derivatives and
agrochemicals.1 The lipophilicity and bioavailability of
bioactive molecules are enhanced upon introducing SCF3
their subsequent trifluoromethylthiolation using a trifluorome-
thanesulfenamide reagent (Scheme 1c).6 2-Trifluoromethylth-
group(s).2 Therefore, many recently developed bioactive
iopyridine derivatives have also been obtained via nucleophilic
trifluoromethylthiolation of aryl halides using a trifluoromethyl
copper reagent (Scheme 1d).7 The trifluoromethyl copper
complex can be generated in situ using a catalytic amount of
CuCl, bipyridyl, Me3SiCF3, and Na2S2O3. 2-Trifluoromethylth-
iopyridine can be synthesized via the trifluoromethylthiolation
of 2-iodopyridine under copper catalysis (Scheme 1e).8
Trifluoromethylthio groups can also be introduced into
pyridine skeletons via a directing group-assisted copper-
mediated C−H trifluoromethylthiolation reaction (Scheme
1f).9 Herein, we report the regioselective C−H trifluorome-
thylthiolation of pyridine, quinoline, and their related
compounds (Scheme 1g).10
molecules contain SCF3 group(s) (Figure 1).
We initially investigated the regioselective C−H trifluor-
omethylthiolation of quinoline based on our previously
reported study.11−13 However, the desired reaction did not
proceed using quinoline N-oxide or quinoline N-oxide·BF2CF3
complex with AgSCF3 (or a mixture of AgSCF3 and an
additive; see the Supporting Information for details).
Subsequently, we changed the additive used to electrophili-
cally activate the quinoline ring. The reaction of quinoline N-
oxide (1a) with AgSCF3 in the presence of 1.1 equiv of o-NsCl
in toluene at 25 °C for 16 h gave a mixture of 2-, 3-, and 4-
trifluoromethylthiolated quinolines (2a, 3a, and 4a, respec-
tively) in yields of 19%, 4%, and 5%, respectively (Table 1,
entry 1). The yield of 2a increased by changing the solvent
(Table 1, entries 2−6) with acetonitrile affording the best
Figure 1. Several examples of bioactive molecules with a
trifluoromethylthio group.
Several methods have been used to synthesize aromatic and
heteroaromatic compounds bearing trifluoromethylthio groups
(Scheme 1).3 2-Trifluoromethylthiopyridine can be synthe-
sized via trifluoroacetylation of thiohydroxamic acid, followed
by a decarboxylative rearrangement (Scheme 1a).4 There have
been several reports on the S-trifluoromethylation of
dithiodipyridine using trifluoroiodomethane as a trifluorome-
thylation reagent (Scheme 1b).5 Trifluoromethylthiolated
Received: April 27, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01474
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Several Examples of C−H
Trifluoromethylthiolation
Table 1. Investigation of Several Solvents and Additives
a
1a (0.20 mmol) was treated with a solution of AgSCF3 (1.1 equiv)
b
and an additive (1.1 equiv) in a solvent (1.0 mL) at 25 °C. Isolated
yield.
(CH3CN, δ = −20.9 ppm) was significantly shifted to −45.7
ppm upon mixing with 2,4-dinitrobenzenesulfonyl chloride,
and AgCl was not formed as a white precipitate during the
reaction. These results indicate that complex A (Scheme 4)
must be an important intermediate. In addition, the reaction of
1a with 4-(NO2)C6H4SO2SCF3 (5) gave 2a in <5% yield
(Scheme 3), which indicated that 5 is not a reaction
intermediate.
The proposed mechanism based on these results is shown in
Scheme 4. Complex A is formed from 2,4-dinitrobenzene-
sulfonyl chloride and AgSCF3, which then reacts with 1 via a
seven-membered transition state to give adduct B, accom-
panied by the formation of AgCl. The elimination of 2,4-
dinitrobenzenesulfonic acid from intermediate B gives the 2-
trifluoromethylthiolated product 2.
The regioselective C−H trifluoromethylthiolation reaction
proceeds in good yield, even on a gram-scale (Scheme 5).
Treating 1.05 g of quinoline N-oxide (1a) with AgSCF3 in the
presence of 2,4-dinitrobenzenesulfonyl chloride gave 1.02 g of
2-(trifluoromethylthio)quinoline (2a) in 62% yield (Scheme
5). The yield of 2a was similar to that observed in the small-
scale reaction (61% yield; 1a: 0.200 mmol, 29.0 mg).
The reaction was applied to the regioselective C−H
trifluoromethylthiolation of quinidine derivative (Scheme 6).
Treatment of O-benzyl quinidine N-oxide (6) with AgSCF3 in
the presence of 2,4-dinitrobenzenesulfonyl chloride in
acetonitrile gave O-benzyl trifluoromethylthioquinidine (7) in
90% yield without the loss of the functional groups. This result
shows that the C−H trifluoromethylation reaction can be used
in the late-stage transformation of bioactive molecules.
result (Table 1, entry 5). We then investigated several additives
to improve the yield and selectivity of 2a (Table 1, entries 7−
10). As a result, 2,4-dinitrobenzenesulfonyl chloride gave the
best yield and selectivity of 2a.
We then investigated the substrate scope of the six-
membered heteroaromatic compounds used in the reaction
(Scheme 2). Quinoline derivatives bearing a methyl group at
the 3-, 4-, 6-, or 8-position (corresponding to 1b, 1c, 1d, or 1e,
respectively) gave the desired 2-trifluoromethylthiolated
products in yields of 50%−73%. The yield of 2e was lower
than that observed for 2c and 2d, which was attributed to the
steric hindrance. The desired reaction proceeded in good yield
without the loss of the functional groups using quinoline
derivatives bearing a halogen atom (F, Cl, Br, and I) and
methoxy carbonyl, cyano, and methoxy groups. Pyridine
derivatives 2m and 2n were also obtained in good yield.
Other heteroaromatic N-oxides derived from pyrimidine and
benzoquinolines were successfully converted to their corre-
sponding trifluoromethylthiolated products 2o−2q in moder-
ate to good yield.
To obtain mechanistic insight of the reaction, we performed
several experiments. The 19F NMR chemical shift of AgSCF3
B
DOI: 10.1021/acs.orglett.9b01474
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Substrate Scope of 2-Position-Selective C−H
Scheme 5. Gram-Scale Reaction
a
Trifluoromethylthiolation
Scheme 6. Trifluoromethylthiolation of the Quinidine
Derivative
useful methods to introduce triflyl group(s) into hetero-
aromatic compounds.15 After trifluoromethylthiolation of
quinoline N-oxide (1a), ruthenium-catalyzed oxidation of the
resulting product 2a (without isolation) gave the correspond-
ing trifluoromethanesulfonylated quinoline 8 in 62% yield
(Scheme 7).
Scheme 7. Introduction of the Trifluoromethanesulfonyl
Group
a
1 (0.20 mmol) was treated with a solution of AgSCF3 (1.1 equiv)
and 2,4-(NO2)2C6H3SO2Cl (1.1 equiv) in CH3CN (1.0 mL) at 25
b
°C. AgSCF3 (1.5 equiv), 2,4-(NO2)2C6H3SO2Cl (1.6 equiv), 80 °C.
c80 °C.
Scheme 3. Reaction of 1a with ArSO2SCF3 (5)
In summary, we have successfully performed the regiose-
lective C−H trifluoromethylthiolation of pyridine, quinoline,
and their related six-membered heteroaromatic-N-oxides in the
presence of 2,4-dinitrobenzenesulfonyl chloride, using AgSCF3
as a trifluoromethylthiolation reagent. By using this reaction,
the desired trifluoromethylthiolated products were obtained in
good yield, even on a gram-scale, with good functional group
tolerance. The regioselective C−H trifluoromethylthiolation of
quinidine derivative was also demonstrated, and the result
shows that the C−H trifluoromethylthiolation reaction can be
used in the late-stage transformation of bioactive molecules.
The trifluoromethylthio group can easily be oxidized to the
corresponding trifluoromethanesulfonyl (triflyl) group, which
is a useful functional group in organic functional materials,
such as bioactive molecules. We hope that this reaction will
become a useful method to synthesize trifluoromethylthio-
group-containing six-membered heteroaromatic compounds.
Scheme 4. Proposed Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01474.
The trifluoromethanesulfonyl (triflyl) group is a useful
functional group in organic functional materials, such as
bioactive molecules.14 Therefore, it is important to develop
1
Experimental procedures, characterization data, and H
and 13C NMR spectra for new compounds (PDF)
C
DOI: 10.1021/acs.orglett.9b01474
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Castro, A.; Luetje, C. W.; Damaj, M. I.; Mascarella, S. W.; Navarro, H.
A.; Carroll, F. I. J. Med. Chem. 2012, 55, 6512−6522.
(15) Guyon, H.; Chachignon, H.; Cahard, D. Beilstein J. Org. Chem.
2017, 13, 2764−2799.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kuninobu@cm.kyushu-u.ac.jp.
ORCID
Takeru Torigoe: 0000-0002-4902-1596
Yoichiro Kuninobu: 0000-0002-8679-9487
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by JSPS Kakenhi (Grant Nos.
JP 17H03016 and JP 18H04656) and the Takeda Science
Foundation.
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DOI: 10.1021/acs.orglett.9b01474
Org. Lett. XXXX, XXX, XXX−XXX