Stereoselective Photoredox-Catalyzed Chlorotrifluoromethylation of Alkynes: Synthesis of Tetrasubstituted Alkenes

Article abstract of DOI:10.1021/acs.orglett.7b00470

A new photoredox-catalyzed chlorotrifluoromethylation reaction of internal arylalkynes under mild conditions using visible light has been developed. The reactions proceed with high levels of regio- and stereoselectivity and utilize commercially available CF₃SO₂Cl as both the CF₃ and Cl source. In the mechanistic pathway for this process, generation of the CF₃ radical and chloride ion occurs by Ir(ppy)₃-photocatalyzed reductive decomposition of CF₃SO₂Cl. The synthetically important trifluoromethyl-substituted vinyl chlorides produced in this process can be readily transformed to 1,1-bis-arylalkenes by using Suzuki coupling.

Full text of DOI:10.1021/acs.orglett.7b00470

Letter
pubs.acs.org/OrgLett
Stereoselective Photoredox-Catalyzed Chlorotrifluoromethylation of
Alkynes: Synthesis of Tetrasubstituted Alkenes
Hong Sik Han,†,‡,§ Young Jin Lee,†,‡,§ Young-Sik Jung,†,‡ and Soo Bong Han*,†,‡
†Division of Bio & Drug Discovery, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong, Daejeon 34114,
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: A new photoredox-catalyzed chlorotrifluoromethyla-
tion reaction of internal arylalkynes under mild conditions using
visible light has been developed. The reactions proceed with high
levels of regio- and stereoselectivity and utilize commercially
available CF3SO2Cl as both the CF3 and Cl source. In the
mechanistic pathway for this process, generation of the CF3 radical
and chloride ion occurs by Ir(ppy)3-photocatalyzed reductive
decomposition of CF3SO2Cl. The synthetically important trifluor-
omethyl-substituted vinyl chlorides produced in this process can be readily transformed to 1,1-bis-arylalkenes by using Suzuki
coupling.
Scheme 1. Synthesis of Trifluoromethyl, Halogen-
Substituted Tetrasubstituted Alkenes
etrasubstituted alkenes are among the most useful
1
Tstructural motifs in organic synthesis. Tetrasubstituted
alkenes that contain a CF3 group are particularly useful
intermediates2 in the synthesis of pharmaceutical and agro-
chemical agents as well as substances used in material science
because of their unique properties including modulated
lipophilicity, binding selectivity, and metabolic stability.3
Perhaps the most useful approaches that can be envisaged for
preparation of CF3-containing tetrasubstituted alkenes are
those in which a halogen is simultaneously introduced because
the presence of this group would facilitate further functionaliza-
tion reactions (Scheme 1).
However, methods for introduction of halogen and CF3 in
one process are limited and usually involve multistep
sequences. For example, Lu devised a multistep route to
prepare alkenes that contain CF3 and Br groups. In this
sequence, reaction of ethyl trifluoromethylpyruvate with CBr4
and DIBAL-H produces a 1,1-dibromoalkene, which then
undergoes selective lithiation and alkylaion to form the desired
alkene (Scheme 1, eq 1).4 Similarly, Shimizu used a cross-
coupling arylation reaction of dibromoalkenes, which are
prepared from a CF3-substituted ketone (Scheme 1, eq 2).5
In another approach, nucleophilic addition of an organolithium
and NCS to trifluoromethyl phosphoranes is utilized to
generate chloro- and CF3-substituted alkenes.6
In this sequence, the required phosphoranes are formed in
advance from the corresponding anhydrides (Scheme 1, eq 3).7
The protocols described above have several disadvantageous
features including their multistep nature and required use of
unstable organometallic species. Consequently, the develop-
ment of a concise, versatile, and stereoselective method for the
synthesis of tetrasubstituted alkenes that contain halogen and
CF3 groups would be significant. In the studies described
below, we developed a novel and facile visible-light-promoted
photoredox-catalyzed process8 that generates products in this
family. The one-step method utilizes CF3SO2Cl as both the
CF3 and Cl source (Scheme 1, eq 4).
The strategy used to design the new approach to prepare
CF3- and Cl-containing tetrasubstituted alkenes was based on
the results of a previous study which led to the successful
Received: February 15, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00470
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
development of a photoredox-catalyzed alkene functionalization
process.9 We believed that CF3SO2Cl10 would serve as both a
CF3 and halogen source in this process. Importantly, CF3SO2Cl
is relatively inexpensive and convenient to use (liquid) in
contrast with other substances such as CF3I (gas), Umemoto’s
reagents, and Togni’s reagents.11 We anticipated that the new
reaction would follow the photocatalyzed redox sequence
displayed in Scheme 2. In the route, the excited state of the
Table 1. Optimization of the Chlorotrifluoromethylation
Reaction of Alkynes
a
Scheme 2. Proposed Pathway for Direct
Trifluoromethylchlorination Reactions of Internal Alkynes
photoredox catalyst (*Mn), generated by visible light
absorption, would donate an electron to CF3SO2Cl to form a
radical anion that fragments to yield the CF3 radical and
chloride ion.
a
The reactions were carried out under N2 atmosphere at 25 °C for 12
b
h using 1a (0.1 mmol) and CF3SO2Cl (0.15 mmol). Yields were
determined by H NMR. Isolated yield. In the dark.
c
d
1
We anticipated that addition of the CF3 radical to an alkyne
would occur regioselectively to produce an aryl ring stabilized
vinyl radical.12 If Mn+1 has an appropriate reduction potential, it
would accept an electron from the vinyl radical to generate a
vinyl cation and regenerate the photocatalyst Mn. Finally,
addition of chloride to the vinyl cation would yield the target
tetrasubstituted alkene. We also anticipated that because of
electrostatic repulsion, chloride addition would take preferen-
tially from a direction anti to the CF3 group.13
To test this proposal, a mixture of the unsymmetrical alkyne
1a and CF3SO2Cl, containing K2HPO4 as a base and Ru(bpy)3
as the catalyst in MeCN was subjected to visible light
irradiation using blue LEDs. As predicted, this process leads
to formation of the desired alkene 2a in 58% yield (Table 1,
entry 1). A screen of various catalysts led to identification of
fac-Ir(ppy)3 as being optimal (67% yield, entries 2−4). The
results of further optimization studies showed that Li2CO3 (0.5
equiv) and acetone are ideal base and solvent combinations
(78%, entry 9). In the absence of visible light irradiation, none
of the desired product is formed (entry 10). Moreover,
irradiation of a mixture not containing the photocatalyst leads
to formation of a lesser amount of 2a (23%, entry 11), likely
arising through an inefficient radical chain pathway promoted
by direct light absorption by CF3SO2Cl. To clarify the
mechanistic insight, a quantum yield of the reaction was
determined. The quantum yield for the formation of 2a is 0.36,
which supports the photocatalytic cycle. However, more
detailed mechanistic study is necessary to confirm the reaction
cycle.14 The regioselective nature of the process was confirmed
by X-ray crystal analysis of a product.15
The alkyne scope of the process, carried out using the
optimized conditions, was examined (Table 2, 1a−k). The
results show that the reaction takes place efficiently using
substrates that contain a variety of arene ring substituents. For
example, reactions of alkynes containing acetyl-, p-tosyl-, and
Boc-protected amine-substituted aryl groups undergo the
reaction efficiently (74%, 85%, and 78% yields, respectively,
Table 2, 2a−c). Furthermore, important functional groups such
as an ether (70%, 2d), triflate (58%, 2e), cyano (62%, 2f), ester
(71%, 2g), nitro (79%, 2h), and alkyl (62%, 2i) are unaltered
by and do not affect the process. Notably, alkynes containing
halogens 2j (Br, 53%) and 2k (Cl, 66%) are efficiently
transformed to the desired products.
We also explored reactions of 4-acetaminophenylalkynes that
contain various R groups at the nonaryl-substituted position
(Table 3). The results demonstrate that while primary alkyl
groups are well tolerated (Me (2a, 74%) and n-Bu (4a, 70%)),
substrates possessing secondary and tertiary alkyl groups
including cyclohexyl (4b, 60%), cyclopentyl (4c, 44%), and t-
Bu (4d, 44%) react with lower efficiencies. This is attributed to
a steric effect that influences the rates of CF3 radical addition.
In addition, amide (4e, 63%) and ester (4f, 44%) group
containing alkynes react with good to moderate efficiencies.
Moreover, the unprotected hydroxymethyl-substituted alkene is
B
DOI: 10.1021/acs.orglett.7b00470
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 2. Chlorotrifluoromethylation of Alkynes I
Table 3. Chlorotrifluoromethylation of Alkynes II
a
Reactions were carried out under N2 atmosphere at room
temperature for 12 h using alkyne (0.1 mmol) and CF3SO2Cl (0.15
b
mmol). Isolated yield after purification by chromatography on SiO2.
c
d
1
Yields were determined by using H NMR Reaction provided E/Z
e
mixture of stereoisomers. 0.2 mmol scale of alkyne.
generated in high yield (4g, 73%). Interestingly, when a CF3-
substituted alkyne 3h was submitted to the reaction conditions,
the 1,1-bis-CF3-substituted alkene is produced (4h, 55%). The
terminal alkyne 3i yields the target 4i in only 34% yield along
with a complicated mixture of unidentified byproducts.
To demonstrate how the new methodology can be
incorporated into sequences to prepare complex targets, alkene
a
The reactions were carried out under N2 atmosphere at room
temperature for 12 h using alkyne (0.1 mmol) and CF3SO2Cl (0.15
b
c
d
mmol). 1 mmol scale. Isolated yield. CF3SO2Cl (0.20 mmol) was
used. 0.2 mmol scale of alkyne. Initially 0.1 mmol CF3SO2Cl was
added. After 3 h, another 0.1 mmol of CF3SO2Cl was added.
e
f
C
DOI: 10.1021/acs.orglett.7b00470
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2a was utilized in Suzuki coupling reactions16 with various
boronic acids (Scheme 3). As expected, the chloro group in 2a
ACKNOWLEDGMENTS
This work was supported by the Korea Research Institute of
Chemical Technology (KK-1703-C00 and KK-1706-G08).
■
Scheme 3. Pd-Catalyzed Suzuki Reaction
REFERENCES
■
(1) For recent reviews on tetrasubstituted alkene, see: (a) Gigant, N.;
Quintin, F.; Backvall, J.-E. J. Org. Chem. 2015, 80, 2796. (b) Tietze, L.
̈
F.; Hungerland, T.; Eichhorst, C.; Dufert, A.; Maaß, C.; Stalke, D.
̈
Angew. Chem., Int. Ed. 2013, 52, 3668. (c) Liu, P.; Seo, J. H.; Weinreb,
S. M. Angew. Chem., Int. Ed. 2010, 49, 2000. (d) Negishi, E. I.; Huang,
Z.; Wang, G.; Mohan, S.; Wang, C.; Hattori, H. Acc. Chem. Res. 2008,
41, 1474. (e) Flynn, A. B.; Ogilvie, W. W. Chem. Rev. 2007, 107, 4698.
(f) Reiser, O. Angew. Chem., Int. Ed. 2006, 45, 2838. (g) Yu, H.;
Richey, R. N.; Carson, M. W.; Coghlan, M. J. Org. Lett. 2006, 8, 1685.
(h) Jordan, V. C. J. Med. Chem. 2003, 46, 1081.
(2) (a) Ma, J.; Yi, W.; Lu, G.; Cai, C. Adv. Synth. Catal. 2015, 357,
3447. (b) Monostory, K.; Jemnitz, K.; Vereczkey, L.; Czira, G. Drug
Metab. Dispos. 1997, 25, 1370.
(3) (a) Wang, J.; Sanchez-Rosello, M.; Acena, J. L.; Del Pozo, C.;
́
́
̃
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev.
2014, 114, 2432. (b) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308.
(c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
a
The reactions were carried out under N2 atmosphere at 90 °C for 18
Rev. 2008, 37, 320. (d) Muller, K.; Faeh, C.; Diederich, F. Science
̈
h using 2a (0.1 mmol), Pd2dba3 (5 mol %), XPhos (10 mol %), K3PO4
(3.0 equiv), relevant R-B(OR′)2 (2.0 equiv), and toluene (0.5 mL).
2007, 317, 1881. (e) Jeschke, P. ChemBioChem 2004, 5, 570.
(4) Li, Y.; Lu, L.; Zhao, X. Org. Lett. 2004, 6, 4467.
b
The reaction was carried out under N2 atmosphere at 90 °C for 18 h
(5) Takeda, Y.; Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2007,
46, 8659.
(6) Shen, Y.; Gao, S. J. Chem. Soc., Perkin Trans. 1 1996, 20, 2531.
using 2a (0.1 mmol), Pd2dba3 (10 mol %), XPhos (20 mol %), K3PO4
(3.0 equiv), relevant R-B(OR′)2 (2.0 equiv), and toluene (0.5 mL).
(7) Hamper, B. C. J. Org. Chem. 1988, 53, 5558.
(8) (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev.
2013, 113, 5322. (b) Narayanam, J. M. R.; Stephenson, C. R. J. Chem.
Soc. Rev. 2011, 40, 102. (c) Zeitler, K. Angew. Chem., Int. Ed. 2009, 48,
9785.
(9) Oh, S. H.; Malpani, Y. R.; Ha, N.; Jung, Y.-S.; Han, S. B. Org. Lett.
2014, 16, 1310.
(10) For use of CF3SO2Cl as a CF3 radical source with visible light,
see: (a) Reiser, O. Acc. Chem. Res. 2016, 49, 1990. (b) Pagire, S. K.;
Paria, S.; Reiser, O. Org. Lett. 2016, 18, 2106. (c) Bagal, D. B.;
Kachkovskyi, G.; Knorn, M.; Rawner, T.; Bhanage, B. M.; Reiser, O.
Angew. Chem., Int. Ed. 2015, 54, 6999. (d) Tang, X.-J.; Dolbier, W. R.
Angew. Chem., Int. Ed. 2015, 54, 4246. (e) Tang, X.-J.; Thomoson, C.
S.; Dolbier, W. R. Org. Lett. 2014, 16, 4594. (f) Nagib, D. A.;
MacMillan, D. W. C. Nature 2011, 480, 224.
serves as the reactive center in these processes that yield 1,1-
diarylalkenes arising from introduction of ethoxyphenyl (5a,
90%), methylpyrazole (5b, 75%), furanyl (5c, 74%), and
benzothiophene (5d, 71%) groups. This sequence provides
versatile method to synthesize complex tetrasubstituted alkenes.
In summary, the studies described above have led to the
development of a new, facile, and stereo- and regioselective
method for the preparation of CF3- and Cl-containing
tetrasubstituted alkenes. The efficiency and concise nature of
the process, along with the mild conditions employed, serve as
major advantages of the new approach. The ability to use
commercially available liquid CF3SO2Cl as CF3 and Cl sources
makes the method highly attractive and significant.
(11) For Umemoto’s reagents and Togni’s reagents, see: (a) Wiehn,
M. S.; Vinogradova, E. V.; Togni, A. J. Fluorine Chem. 2010, 131, 951.
(b) Koller, R.; Stanek, K.; Stolz, D.; Aardoom, R.; Niedermann, K.;
Togni, A. Angew. Chem., Int. Ed. 2009, 48, 4332. (c) Kieltsch, I.;
Eisenberger, P.; Togni, A. Angew. Chem., Int. Ed. 2007, 46, 754.
(d) Umemoto, T.; Adachi, K.; Ishihara, S. J. Org. Chem. 2007, 72,
6905. (e) Eisenberger, P.; Gischig, S.; Togni, A. Chem. - Eur. J. 2006,
12, 2579. (f) Ono, T.; Umemoto, T. J. Fluorine Chem. 1996, 80, 163.
(g) Umemoto, T.; Ishihara, S.; Adachi, K. J. Fluorine Chem. 1995, 74,
77. (h) Umemoto, T.; Ishihara, S. J. Am. Chem. Soc. 1993, 115, 2156.
(i) Teruo, U.; Sumi, I. Tetrahedron Lett. 1990, 31, 3579.
(12) Lovett, G. H.; Sparling, B. A. Org. Lett. 2016, 18, 3494.
(13) (a) Tomita, R.; Koike, T.; Akita, M. Angew. Chem., Int. Ed. 2015,
54, 12923. (b) Iqbal, N.; Jung, J.; Park, S.; Cho, E. J. Angew. Chem., Int.
Ed. 2014, 53, 539.
(14) In the case of electron-withdrawing substituents on an aromatic
ring, a radical-chain pathway is possibly a main reaction pathway due
to the difficult oxidation of the corresponding vinyl radical. See the
Supporting Information for the detail of a quantum yield
determination.
(15) An X-ray crystal structure of 2b was obtained. See the
Supporting Information for details.
(16) (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981,
11, 513. (b) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett.
1979, 20, 3437.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00470.
■
S
X-ray data for compound 2b (CIF)
Detailed experimental procedures and characterization
for all new compounds as well as spectral and X-ray
crystallographic data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sbhan@krict.re.kr.
ORCID
Soo Bong Han: 0000-0002-7831-1832
Author Contributions
§H.S.H. and Y.J.L. contributed equally.
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.7b00470
Org. Lett. XXXX, XXX, XXX−XXX