Visible-Light-Induced Arylthiofluoroalkylations of Unactivated Heteroaromatics and Alkenes

Article abstract of DOI:10.1021/acs.orglett.6b01495

Visible-light-induced arylthiofluoroalkylations of unactivated heteroaromatics and alkenes have been developed utilizing readily available arylthiofluoroalkyl sources. This method enables simultaneous installation of sulfur and fluoroalkyl moieties, two important functional groups, which demonstrates its potential use for late-stage modifications in the synthesis of functional molecules. This method can be easily utilized to fine-tune the properties of lead molecules in drug development by controlling the number of fluorine atoms in the reagents.

Full text of DOI:10.1021/acs.orglett.6b01495

Letter
pubs.acs.org/OrgLett
Visible-Light-Induced Arylthiofluoroalkylations of Unactivated
Heteroaromatics and Alkenes
Yeojin Choi,∥,† Chunghyeon Yu,∥,‡ Jun Soo Kim,§ and Eun Jin Cho*,†
†Department of Chemistry, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Republic of Korea
‡Department of Bionanotechnology, Hanyang University, Ansan 15588, Republic of Korea
§Department of Chemistry & Nanoscience, Ewha Womans University, Seoul 03760, Republic of Korea
S
* Supporting Information
ABSTRACT: Visible-light-induced arylthiofluoroalkylations of unactivated
heteroaromatics and alkenes have been developed utilizing readily available
arylthiofluoroalkyl sources. This method enables simultaneous installation of
sulfur and fluoroalkyl moieties, two important functional groups, which
demonstrates its potential use for late-stage modifications in the synthesis of
functional molecules. This method can be easily utilized to fine-tune the
properties of lead molecules in drug development by controlling the number of
fluorine atoms in the reagents.
luoroalkylation reactions have been of great interest in many
applications due to the ability of the introduced fluoroalkyl
F
groups to change the physical, chemical, and biological activities
of organic compounds.1 These effects have stimulated the
intensive development of new pharmaceutical and agrochemical
agents bearing the fluoroalkyl moiety.2 Furthermore, the
introduction of fluoroalkyl groups containing sulfur has been
of growing interest because the presence of sulfur can further
change the properties of molecules; for example, inducing high
lipophilicity.3 Figure 1a shows the dramatic increase in activity
against HIV (Human Immunodeficiency Virus)-1 achieved by
incorporation of both sulfur and fluoroalkyl groups into non-
nucleoside reverse transcriptase inhibitors.4 Sulfur is an essential
element of the molecule to ensure biological activity [Figure 1a,
A vs B], and the CF2 motif increases the reactivity significantly
[Figure 1a, C vs D]. Due to the importance of thiofluoroalkyl
moieties, various methods have been developed to construct the
−S(CF2)n− motif. The most common approaches involve
sequential sulfenylation and fluoroalkylation (or vice versa)
reactions.3 Considering the usage of both moieties for drug
development, direct thiofluoroalkylations could offer an efficient
strategy for late-stage modifications [Figure 1b].
Although there have been various methods for direct
thiofluoroalkylations by C−C bond formation,5 many of them
still suffer from limited substrate scope and harsh reaction
conditions including the use of toxic reagents, extremely low or
high temperatures, or a long reaction time. Herein, we report
visible-light-induced6−9 C−C bond formation for arylthiofluoro-
alkylations of unactivated heteroaromatic compounds and
alkenes, where the reactivity was controlled efficiently under
mild conditions with a wide substrate scope [Figure 1c].
For our investigations, we utilized the readily available
phenylthiofluoroalkyl bromides,10 BrCF2SPh (1a),
BrCF2CF2SPh (1b), and BrCF2CF2CF2CF2SPh (1c), as sources
of electron-deficient carbon-centered radicals for visible-light-
Figure 1. (a) Effect of sulfur and fluoroalkyl groups. (b) Strategy for the
addition of sulfur and fluoroalkyl groups. (c) Our methodology by
visible-light photocatalysis.
mediated transformations. Based on the electron density
difference of the key phenylthiofluoroalkyl radical intermediates
obtained by the density functional theory (DFT) calculations
(Figure 2), we could expect differences in reactivity of the
radicals depending on the number of fluoroalkyl carbons (n = 1,
Received: May 24, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01495
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Organic Letters
Letter
a
Table 1. Optimization Studies with 2a
Figure 2. Electrostatic potential maps of 1a′, 1b′, and 1c′ calculated by
DFT method with the B3LYP functional and the 6-31G+(d) basis set.
The color scale represents the electrostatic potential (ESP), and the
values specified with arrows refer to the natural atomic charges of the
corresponding atoms obtained by natural bond orbital (NBO) analysis.
2, or 4). Compared to the radical centers in 1b′ and 1c′ (with
natural atomic charges of 0.746 and 0.757, respectively), that of
1a′ is less electrophilic showing a less positive natural atomic
charge of 0.535. It is likely that the delocalization of the lone pair
of electrons on the sulfur atom increases the electron density
(and decreases the natural charge) of the neighboring carbon
radical in 1a′. The radical centers in 1b′ and 1c′ are located at
greater distances from the sulfur atom and remain highly
electron-deficient, with more positive natural atomic charges
than in the case of 1a′.
Indeed, we observed quite different reactivities among
phenylthiofluoroalkyl radicals toward the phenylthiofluoroalky-
lations by C−C bond formation. In initial studies, we utilized
radical sources 1a and 1b with N-methylpyrrole 2a as the model
substrate (Table 1). The reactions with 1c showed reactivity
similar to those with 1b. For phenylthiodifluoromethylation of
2a using 1a and tetramethylethylenediamine (TMEDA) in
MeCN, a tricyclometalated Ir complex, fac-Ir(ppy)3, showed the
best reactivity while the use of a Ru photocatalyst like
[Ru(phen)3]Cl2 or [Ru(bpy)3]Cl2 provided lower yields of 3aa
(Table 1-I, entries 1−4).
On the other hand, the phenylthiotetrafluoroethylation of 2a
using 1b worked best with [Ru(phen)3]Cl2 (Table 1-II, entries
1−4).11 Regarding bases, phenylthiodifluoromethylation using
1a proceeded well with 2,6-lutidine (Table 1-I, entry 7) while
phenylthiotetrafluoroethylation using 1b did not work at all with
2,6-lutidine, but proceeded well with TMEDA (Table 1-II,
entries 2, 5, and 6). The subtle differences in the combination of
photocatalyst, base, and solvent significantly affected the
reactivity of both phenylthiofluoroalkylation processes. The
results of further optimization studies are available in the
Supporting Information as Tables S1 and S2.
a
b
Reaction conditions: 1a or 1b (0.14 mmol), 2a (0.1 mmol). The
yield was determined by gas chromatography or 19F NMR spectros-
copy with internal standards, dodecane and 4-fluorotoluene,
c
respectively. 3 mol % of [Ru(phen)3]Cl2 was used.
used. A variety of heteroaromatics including pyrrole (entries 1−
3), furan (entry 4), indole (entries 5−9), benzofuran (entry 10),
and benzothiophene (entry 11) underwent phenylthiofluoro-
alkylations in moderate to good yields. Phenylthiomethylated
products were relatively less stable so that the CF2 moieties in
3aa and 3ab were transformed into a carbonyl group,12 and some
decomposition was observed in 3ac and 3af during the
purification process with silica-gel chromatography.
Alkenes were also suitable substrates for phenylthiofluor-
oalkylations, and a difference in reactivity was observed when
reactions were carried out in the presence of 1a and 1b/1c. In the
case of reactions of alkenes with 1a, the same conditions as those
used for heteroaromatics produced either cyclized products 5 or
alkenyl products 6, selectively (Table 3). Reactions of aromatic
alkenes 4a and 4b proceeded to give phenylthiodifluoro-
methylated alkenes 6aa (entry 1) and 6ab (entry 2), respectively,
through oxidation of the benzyl radical intermediate 4′ to the
cation intermediate 4″, followed by a deprotonation step.7b
Interestingly, aliphatic alkenes reacted to produce cyclized
products 5, either by radical or cationic electrophilic substitution
of the tethered phenyl ring in 4′ or 4″ (Table 3, entries 3−6).
The proposed mechanisms for the phenylthiofluoroalkylations of
both heteroaromatics and alkenes are illustrated in Schemes S1
and S2 (SI).
With the optimized conditions in hand, we next evaluated the
phenylthiofluoroalkylations of various heteroaromatics (Table
2). A combination of 2 mol % fac-Ir(ppy)3 and 2 equiv of 2,6-
lutidine was used for phenylthiodifluoromethylations with 1.4
equiv of BrCF2SPh (1a) in DMF (0.1 M). On the other hand, for
reactions with 1.4 equiv of BrCF2CF2SPh (1b) or
BrCF2CF2CF2CF2SPh (1c), a combination of 2−3 mol %
[Ru(phen)3]Cl2 and 2 equiv of TMEDA in MeCN (0.1 M) was
B
DOI: 10.1021/acs.orglett.6b01495
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Organic Letters
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Table 2. Substrate Scope for Phenylethiofluoroalkylations of
Heteroaromatics
Table 3. Substrate Scope for Phenylthiodifluoromethylation
of Alkenes
a
a
a
Reaction conditions: 1 (0.7 mmol), 2 (0.5 mmol). A: fac-Ir(ppy)3 (2
mol %), 2,6-lutidine (2 equiv), DMF (0.1 M). B: [Ru(phen)3]Cl2 (2−
b
a
b
3 mol %), TMEDA (2 equiv), MeCN (0.1 M). Isolated yield.
Reaction conditions: 1a (1.4 equiv), 4 (0.3 or 0.5 mmol). Isolated
c
c
During the silica-gel column chromatography process, the CF2 moiety
yield. During the silica-gel column chromatography process, the CF2
was transformed into a carbonyl group.12 The yield was determined
d
moiety was transformed into a carbonyl group.12
by 19F NMR spectroscopy due to some decomposition of the product
e
during silica-gel column chromatography. Numbers in parentheses
indicate yield based on the recovered starting material. 5% of
Table 4. Substrate Scope for Phenylthioperfluoroalkylation of
Alkenes with 1b and 1c
f
a
regioisomers from the substitution at six-membered ring were also
obtained.
On the other hand, the reactions of alkenes with 1b and 1c
required conditions different from those employed for
heteroaromatics.13 A combination of 2 mol % fac-Ir(ppy)3 and
2 equiv TMEDA in DCM (0.2 M) was used to convert alkenes
into alkenyl-phenythiofluoroalkylated products 6 or hydro-
phenylthiofluoroalkylated products 7 (Table 4). For aliphatic
alkenes, reactions typically afforded phenylthiofluoroalkylated
alkanes as major products through hydro-phenylthiofluoroalky-
lations (Table 4, entries 3−6), while the aromatic alkene 4b
yielded alkenyl derivatives 6bb and 6cb as major products (Table
4, entries 1 and 2). In the hydro-thiofluoroalkylations, the tertiary
amine TMEDA acted not only as electron donor in photo-
catalytic step but also as a hydrogen atom source.14 Interesting
results were also obtained by reacting alkenes with 1b and 1c in
an oxygen atmosphere. Such reactions produced sulfoxides as
final products, through further oxidation of the sulfide moiety in
the hydrophenylthiofluoroalkylated products in the presence of
molecular oxygen (see Scheme S3 in the SI).15
a
b
Reaction conditions: 1b or 1c (0.7 mmol), 4 (0.5 mmol). Isolated
c
yield. The formation and the corresponding yield was checked by
GC-MS and H NMR spectroscopy of the crude reaction mixture.
1
In order to show the generality of the transformation, the
arylthiofluoroalkyl reagents were varied next (Scheme 1).
Reactions of 2a with methylphenylthiotetrafluoroethyl bromide
(8) and chlorophenylthiotetrafluoroethyl bromide (10) pro-
C
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Chemistry: From Biophysical Aspects to Clinical Applications; World
Scientific Publishing Company: 2012.
Scheme 1. Variation on Thiofluoroalkyl Sources
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respectively, indicating that the method is applicable to the
synthesis of various arylthiofluoroalkylated products.
In the investigation described above, we have developed
arylthiofluoroalkylation methods for heteroaromatic and alkene
substrates. By using various arylthiofluoroalkyl sources such as
BrCF2SPh, BrCF2CF2SPh, and BrCF2CF2CF2CF2SPh in visible-
light photocatalysis, two functional groups consisting of sulfur
and fluoroalkyl moieties could be simultaneously installed to
unactivated heteroaromatics and alkenes. The reactivity of the
transformation was highly dependent on the electron density of
the carbon-centered radical intermediate of the arylthiofluor-
oalkyl sources. Therefore, different combinations of photo-
catalyst, base, and solvent were employed, depending on the
observed reactivity. The simultaneous introduction of two
functional groups shows the potential use of the method for
late-stage modifications in the development of functional
molecules. In addition, this method can be easily utilized for
fine-tuning of properties in drug development by controlling the
number of fluorine atoms in reagents.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01495.
Experimental details, additional experimental results,
analytic data for arylthiofluoroalkylated compouds and
NMR spectra (PDF)
2016, 22, 4395. (c) Candish, L.; Pitzer, L.; Gumez-Surez, A. N.; Glorius,
̂
F. Chem. - Eur. J. 2016, 22, 4753.
(9) The Wang group generated −CF2SO2Ph compounds as the
isolable intermediates in their difluoromethylations of heteroaromatics;
see: Su, Y.-M.; Wang, X.-S. Org. Lett. 2014, 16, 2958.
(10) Suda, M.; Hino, C. Tetrahedron Lett. 1981, 22, 1997.
(11) The reactions did not proceed without photocatalyst and visible
light. See Tables S1 and S2 in the Supporting Information.
(12) (a) Yang, X.; Fang, X.; Yang, X.; Zhao, M.; Han, Y.; Shen, Y.; Wu,
F. Tetrahedron 2008, 64, 2259. (b) Kuhakarn, C.; Surapanich, N.;
Kamtonwong, S.; Pohmakotr, M.; Reutrakul, V. Eur. J. Org. Chem. 2011,
2011, 5911.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ejcho@cau.ac.kr.
Author Contributions
∥Y.C. and C.Y. contributed equally.
Notes
The authors declare no competing financial interest.
(13) The optimization process was presented as Table S3 in the
Supporting Information.
ACKNOWLEDGMENTS
(14) The [NR3]•+ species formed by the photocatalytic pathway bears
acidic α-hydrogen atoms, and it can also serve as a hydrogen donor; see:
refs 7a, b, e, and (a) Du, J.; Espelt, L. R.; Guzei, I. A.; Yoon, T. P. Chem.
Sci. 2011, 2, 2115. (b) Kim, H.; Lee, C. Angew. Chem., Int. Ed. 2012, 51,
12303.
■
This work was supported by the National Research Foundation
of Korea [NRF-2014R1A1A1A05003274, NRF-2014-011165,
and NRF-2012M3A7B4049657] and Dr. Naeem Iqbal (National
Institute of Biotechnology and Genetic Engineering, Pakistan)
for technical assistance.
(15) Zen, J.-M.; Liou, S.-L.; Kumar, A. S.; Hsia, M.-S. Angew. Chem., Int.
Ed. 2003, 42, 577.
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