Vicinal difunctionalization of alkenes: Chlorotrifluoromethylation with CF3SO2Cl by photoredox catalysis

Article abstract of DOI:10.1021/ol403716t

Photoredox-catalyzed vicinal chlorotrifluoromethylation of alkene is described. In the presence of Ru(Phen)₃Cl₂, CF ₃SO₂Cl was used as a source for the CF₃ radical and chloride ion under visible light irradiation. Various terminal and internal alkenes were transformed to their vicinal chlorotrifluoromethylated derivatives. Biologically active compounds were applied under the condition to obtain desired products, suggesting that the method could be feasible for late-stage modification in drug discovery.

Full text of DOI:10.1021/ol403716t

Letter
pubs.acs.org/OrgLett
Vicinal Difunctionalization of Alkenes: Chlorotrifluoromethylation
with CF3SO2Cl by Photoredox Catalysis
Se Hwan Oh,†,§ Yashwardhan R. Malpani,†,‡,§ Neul Ha,†,‡ Young-Sik Jung,*,†,‡ and Soo Bong Han*,†,‡
†Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong, Daejeon 305-600,
Republic of Korea
‡Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, 217 Gajeongro, Yuseong, Daejeon
305-355, Republic of Korea
S
* Supporting Information
ABSTRACT: Photoredox-catalyzed vicinal chlorotrifluoromethyla-
tion of alkene is described. In the presence of Ru(Phen)3Cl2,
CF3SO2Cl was used as a source for the CF3 radical and chloride ion
under visible light irradiation. Various terminal and internal alkenes
were transformed to their vicinal chlorotrifluoromethylated
derivatives. Biologically active compounds were applied under the
condition to obtain desired products, suggesting that the method
could be feasible for late-stage modification in drug discovery.
tion of alkenes with CF3SO2Cl,9 incorporating not only the CF3
hotoredox catalysis for organic transformations has
Pbecome one of the fast growing fields in organic group but also Cl in one pot, releasing SO2 as a single
chemistry.1 In particular, the difunctionalization of alkenes2
byproduct. This transformation provides a mild and facile
method for introduction of the CF3 and Cl group together,
involving the formation of a C−CF3 bond by photoredox
which is a useful moiety in the field of drug discovery.10
catalysis has become an important area due to its applicability
to pharmaceuticals and agrochemicals.3 Recently, halotrifluoro-
We initially examined the difunctionalization of 1a with 1.5
methylation,4 hydrotrifluoromethylation,5 oxytrifluoromethyl-
equiv of CF3SO2Cl under visible light irradiation (Table 1).
ation,6 and aminotrifluoromethylation7 have been developed
The reaction proceeded smoothly to give the chlorotrifluor-
with CF3I or Umemoto’s reagent8 as a CF3 radical source
omethylated product 2a in 99% yield after 15 h when 1 mol %
of Ru(Phen)3Cl2 was used as a photocatalyst with 0.3 equiv of
(Scheme 1). However, these reagents generally show one or
K2HPO4 (Table 1, entry 3). The K2HPO4 was possibly
more limitations such as the handling of CF3I (gas) and
buffering the reaction system. Other photocatalysts, such as
generation of stoichiometric byproduct (dibenzothiophene
Ru(bpy)3Cl2·6H2O and Ir(ppy)3, also gave the desired
from Umemoto’s reagent). Therefore, a convenient and mild
CF3 radical source is needed. In this context, we have
developed a new photoredox-catalyzed vicinal difunctionaliza-
products in 74% and 99% yields, respectively (entries 4 and
5). MeCN and DCM were found to be optimal solvents based
on solvent screening (entries 3, 6, and 7). When the reaction
was performed without the photoredox catalyst, no product was
obtained (entry 8). Also, in the absence of irradiation no
desired product was generated (entry 9). These controlled
Scheme 1. Difunctionalization of Alkenes with C−CF3 Bond
Formation
experiments clearly showed that a photocatalyst and visible
light irradiation are essential for the transformation.
Having the optimized conditions in hand, we examined the
scope of the method (Table 2). In general, terminal alkenes
showed high reactivity under the condition. Alkenes containing
N-tosyl- and Boc-protected amines were smoothly chlorotri-
fluoromethylated in 99% and 91% yields, respectively (entries 1
and 2). Also, a phthalimide group was not detrimental to the
desired product formation (88% yield, entry 3). A simple
phenyl-containing alkene such as 4-phenyl-1-butene 1d was
efficiently transformed into the desired product in 81% yield
(entry 4). Notably, unprotected hydroxyl and formyl groups
Received: December 23, 2013
Published: February 26, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Table 1. Optimization of Chlorotrifluoromethylation of
Alkenes
Table 2. Scope of Chlorotrifluoromethylation of Terminal
Alkenes
a
a
a
The reactions were carried out under N2 atmosphere at 25 °C for 15
b
h using 1a (0.25 mmol) and CF3SO2Cl (0.375 mmol). Yields were
determined by H NMR. In the dark.
c
1
were very tolerant under the reaction conditions giving 75%
and 83% yields, respectively (entries 5 and 6). Furthermore,
alkenes with ether, ester, and amide functional groups produced
the desired products in high yield (entries 7−11). Also,
compounds with halogen groups on the aromatic ring showed
high stability under the reaction conditions (98%, 80%, and
92% yields, entries 9−11). Surprisingly, a quinoline containing
alkene 1l was converted to its CF3, Cl derivative 2l in high yield
(76%) without any CF3 substitution on the aromatic ring
system (entry 12).9a In addition, we scaled up the reaction with
1i (2.5 mmol scale) and obtained the desired product 2i
quantitatively (entry 9). It demonstrates that this trans-
formation can be conducted beyond the discovery scale.
To expand the scope of the method, 1,1-disubstituted
alkenes were tested under the same reaction conditions (Table
3, entries 1−3). Interestingly, a chloride-containing quaternary
carbon center was generated with the substrates. For example,
unprotected hydroxyl-containing alkene 3a regioselectively
produced the desired product 4a in good yield (78%, entry
1). Carvone that had an enone functional group produced the
desired product 4b in moderate yield (54%, 1:1 dr, entry 2). In
addition, (S)-(−)-perillaldehyde 3c was smoothly converted to
the product 4c in excellent yield (80%, 1:1 dr, entry 3).
Furthermore, internal alkenes were subjected to the reaction
conditions. Symmetric alkenes 3d and 3e generated the desired
product 4d and 4e in good yield (71% and 61%, entries 4 and
5). In the case of asymmetric alkene 3f, only one regioisomer 4f
was produced in moderate yield (62%, entry 6). The
regioselectivity can be explained by the attack of CF3 radical
to the less hindered carbon and the generation of the more
stable tertiary radical.
a
The reactions were carried out under N2 atmosphere at room
temperature for 15 h using alkene (0.25 mmol) and CF3SO2Cl (0.75
b
mmol). Isolated yield after purification by chromatography on SiO2.
c
d
e
CF3SO2Cl (0.375 mmol) was used. Reaction time is 24 h. 2.5 mmol
scale.
This protocol offers the possibility of late-stage difunction-
alization of biologically active compounds that contain alkene
functional groups (Scheme 2). For example, rotenone, which
has been used as an effective pesticide, was smoothly converted
to its Cl- and CF3-substituted derivative (92% yields). Also,
active insecticide (+)-nootkatone was changed to the desired
product (69% yield). These examples show the high functional
group tolerance and the feasibility of the method toward
complicated biologically active compounds.
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Organic Letters
Letter
Table 3. Scope of Trifluoromethyl Chlorination of 1,1-
Disubstituted and Internal Alkenes
Scheme 3. Proposed Mechanism of
Chlorotrifluoromethylation of Alkenes
a
a
The reactions were carried out under N2 atmosphere at room
temperature for 15 h using alkene (0.25 mmol) and CF3SO2Cl (0.375
b
mmol). Isolated yield after purification by chromatography on SiO2.
c
d
e
f
1:1 dr. 1.9:1 dr. Yields were determined by 1H NMR. With
versus SCE) acted as a oxidant to produce the carbocation
intermediate II, and Ru(Phen)3 was regenerated. The
CF3SO2Cl (0.75 mmol).
2+
resulting carbocation was trapped by Cl− to generate the
product. Even though the oxidative quenching mechanism is
plausible, the radical-chain propagation mechanism can not be
ruled out.14 To investigate the significance of the chain
propagation mechanism, an on/off visible light irradiation
experiment was performed. The graph clearly shows that the
transformation required continuous irradiation with visible light
(Scheme 3). Although the possibility of the chain propagation
mechanism is not completely excluded, this result indicates that
radical-chain propagation is not a significant pathway for
product formation. Furthermore, the determined quantum
yield for the formation of 2b is 0.34, which is supporting
evidence for the proposed mechanism.15
Scheme 2. Application to Biologically Active Compounds
Containing an Alkene Functional Group
In conclusion, we have developed a new photoredox-
catalyzed vicinal chlorotrifluoromethylation of alkenes using
CF3SO2Cl as CF3 and Cl sources. This mild and efficient
process enables various alkenes to be transformed to CF3 and
Cl derivatives regioselectively. In addition, “late-stage trans-
formation” of biologically active compounds was performed to
show the feasibility of the method. Considering the significance
of CF3 and Cl functional groups in medicinal chemistry, our
method could be applicable for drug discovery.
A plausible mechanism of the reaction is described in Scheme
2+
3. Irradiation of Ru(Phen)3 with visible light generated its
2+
excited state *Ru(Phen)32+. Then *Ru(Phen)3 (−0.94 V vs
SCE)11 reduced the triflyl chloride (−0.18 V vs SCE)9a,12 and
was oxidized to Ru(Phen)33+. The CF3SO2Cl radical anion was
13
immediately collapsed to CF3, SO2, and Cl−. The stabilized
•
•
electron-deficient CF3 was added to electron-rich alkene, and
3+
the radical intermediate I was formed. Ru(Phen)3 (+1.31 V
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Organic Letters
Letter
(15) (a) Miyake, Y.; Nakajima, K.; Nishibayashi, Y. J. Am. Chem. Soc.
2012, 134, 3338. (b) Miyake, Y.; Ashida, Y.; Nakajima, K.;
Nishibayashi, Y. Chem. Commun. 2012, 48, 6966.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: ysjung@krict.re.kr.
*E-mail: sbhan@krict.re.kr.
Author Contributions
§These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Korea Research Institute of
Chemical Technology (KK-1307-B3).
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