Intermolecular aminotrifluoromethylation of alkenes by visible-light-driven photoredox catalysis

Article abstract of DOI:10.1021/ol4006272

Intermolecular aminotrifluoromethylation of alkenes catalyzed by [Ru(bpy)₃]²⁺ under visible light irradiation has been explored. The present photocatalytic protocol achieves highly efficient and regioselective difunctionalization of C=C bonds, leading to a variety of β-trifluoromethylamines. The reaction is applied to late-stage aminotrifluoromethylation of steroid and amino acid scaffolds.

Full text of DOI:10.1021/ol4006272

ORGANIC
LETTERS
2013
Vol. 15, No. 9
2136–2139
Intermolecular Aminotrifluoromethylation
of Alkenes by Visible-Light-Driven
Photoredox Catalysis
Yusuke Yasu, Takashi Koike,* and Munetaka Akita*
Chemical Resources Laboratory, Tokyo Institute of Technology, 4259 Nagatsuta,
Midori-ku, Yokohama 226-8503, Japan
koike.t.ad@m.titech.ac.jp; makita@res.titech.ac.jp
Received March 9, 2013
ABSTRACT
Intermolecular aminotrifluoromethylation of alkenes catalyzed by [Ru(bpy)3]2þ under visible light irradiation has been explored. The present
photocatalytic protocol achieves highly efficient and regioselective difunctionalization of CdC bonds, leading to a variety of β-trifluoromethylamines.
The reaction is applied to “late-stage aminotrifluoromethylation” of steroid and amino acid scaffolds.
Alkene difunctionalization, particularly introduction of
two different functional groups across a double bond, is an
attractive method for construction of diverse structures
by a single transformation. Therefore, there have been a
large number of studies on transition-metal-catalyzed 1,2-
difunctionalization of alkenes.1 However, transformations
involving construction of CꢀCF3 bonds are still limited to
halotrifluoromethylation,2 carbotrifluoromethylation,3
hydrotrifluoromethylation,4 and oxytrifluoromethylation5,11c
(Scheme 1). A wide variety of trifluoromethylated derivatives
have been prepared as pharmaceutical and agrochemical
products because a trifluoromethyl (CF3) group can influ-
ence chemical and metabolic stability, lipophilicity, and
binding selectivity.6,7 Thus, there has been considerable
interest in development of new methodologies for highly
efficient and selective incorporation of a CF3 group and a
different functional group into alkenes.
~
(1) For recent reviews on alkene difunctionalization, see: (a) Muniz,
K. Chem. Soc. Rev. 2004, 33, 166. (b) Wolfe, J. P. Synlett 2008, 2913. (c)
Jensen, K. H.; Sigman, M. S. Org. Biomol. Chem. 2008, 6, 4083. (d)
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G.; Stahl, S. S. Chem. Rev. 2011, 111, 2981. (f) Wolfe, J. P. Angew.
Chem., Int. Ed. 2012, 51, 10224.
Scheme 1. Vicinal Difunctionalization of Alkenes Involving
Formation of CꢀCF3 Bond
(2) (a) Kamigata, N.; Fukushima, T.; Yoshida, M. J. Chem. Soc.,
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53, 5503. (e) Feng, C.; Loh, T.-P. Chem. Sci. 2012, 3, 3458.
Photoredox catalysis with well-defined ruthenium(II)
polypyridine complexes (e.g., [Ru(bpy)3]2þ) and the rele-
vant cyclometalated iridium(III) derivatives has become a
useful redox method in synthetic chemistry because these
ꢀ
r
10.1021/ol4006272
Published on Web 04/19/2013
2013 American Chemical Society

compounds can undergo visible-light-induced single-electron
transfer (SET).8ꢀ11 Recently, several examples for radical
trifluoromethylation by photoredox catalysis have been
reported, where CF3SO2Cl and gaseous CF3I are used
as the trifluoromethyl radical (•CF3) sources.2d,e,10
On the other hand, we found electrophilic trifluoromethy-
lating (þCF3) reagents such as Umemoto’s reagent 1a
(S-(trifluoromethyl)dibenzothiophenium tetrafluoroborate),12a
Togni’s reagents 1b (1-trifluoromethyl-1,2-benziodoxol-
3-(1H)-one), and 1c (1-trifluoromethyl-1,3-dihydro-3,3-
Table 1. Photoredox-Catalyzed Aminotrifluoromethylation of
Styrene 2aa
•
dimethyl-1,2-benziodoxole)12b,c can also serve as the CF3
precursor in the presence of photoredox catalysts under
visible light irradiation. We have previously reported the
photoredox-catalyzed intermolecular oxytrifluoromethy-
lation of alkenes with þCF3 reagents and O-nucleophiles
via β-trifluoromethylated carbocation intermediates.11c
This interesting result encouraged us to develop a new
difunctionalization of CdC bonds, i.e., aminotrifluoro-
methylation of alkenes, which has not been reported to
date. Herein we first report highly efficient and regioselec-
tive intermolecular aminotrifluoromethylation of alkenes
by photoredox catalysis under visible light irradiation at
room temperature. This photocatalytic protocol enables
practical one-step access to a variety of 1,1,1-trifluoro-3-
acetylaminopropane derivatives, which are important
structural motifs in CF3-containing biologically active
compounds.7,17,19
entry CF3 source
photocatalyst
D2Ob % yield of 3a (4a)c
1
2
3
4
5
6e
7
1a
1b
1c
1a
1a
1a
1a
[fac-Ir(ppy)3]
[fac-Ir(ppy)3]
[fac-Ir(ppy)3]
[fac-Ir(ppy)3]
1 equiv
1 equiv
1 equiv
50 μL
95 (3)
0 (0)
0 (0)
18 (67)
95, 88d
0 (0)
[Ru(bpy)3](PF6)2 1 equiv
[Ru(bpy)3](PF6)2 1 equiv
none
1 equiv
0 (0)
a The reaction was carried out under N2 atmosphere and irradiation
of 425 nm blue LEDs at room temperature using photocatalyst
(2.5 μmol), 1 (50 μmol), 2a (60 μmol), and CD3CN (0.5 mL) in an
NMR tube. b The amount of added D2O is based on the amount of 1.
c Yields were determined by 1H NMR spectroscopy. d Yield of isolated
product from the preparative-scale reaction; see the Supporting Infor-
mation. e In the dark.
We commenced to use acetonitrile (MeCN) as a
N-nucleophile, which is known as an aminative carbocation
trap agent (Ritter-type reaction).13 We initially examined
the photocatalytic reaction of 1.2 equiv of styrene 2a with
1.0 equiv of Umemoto’s reagent 1a using 5 mol % of
photoredox catalyst, [fac-Ir(ppy)3],14 in CD3CN contain-
ing D2O (1 equiv) under visible light irradiation (blue
LEDs: λmax = 425 nm) for 3 h (Table 1). Remarkably,
aminotrifluoromethylated product 3a was obtained in
95% yield as the sole regioisomer, accompanied by forma-
tion of a small amount of hydroxytrifluoromethylated
byproduct 4a (entry 1). The choice of the þCF3 reagent
turned out to be crucial for the present reaction. Togni’s
reagents 1b and 1c gave no aminotrifluoromethylated
product 3a (entries 2 and 3). The amount of water sig-
nificantly affected the yields of 3a. A larger amount of D2O
resulted in formation of a substantial amount of hydro-
xytrifluoromethylated product 4a (entry 4). Another photo-
catalyst, [Ru(bpy)3](PF6)2,15 also promoted the present
reaction, providing the product 3a in 95% NMR yield
(entry 5). The Ru catalyst is less expensive than the Ir
catalyst; thus, we chose the Ru photocatalyst for prepara-
tive experiments and reduced loadings of the catalyst to
0.5 mol %. Under these preparative conditions, product
3a was obtained in 88% isolated yield (entry 5). Notably,
product 3a was not formed either in the dark or in the
(6) Hiyama, T. Organofluorine Compounds: Chemistry and Applica-
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(7) (a) Ojima, I. Fluorine in Medical Chemistry and Chemical Biology;
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2004, 5, 570. (c) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317,
1881.
(8) Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77.
(9) For recent reviews on photoredox catalysis, see: (a) Yoon, T. P.;
Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527. (b) Narayanam, J. M. R.;
ꢀ
Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102. (c) Teply, F. Collect.
Czech. Chem. Commun. 2011, 76, 859. (d) Tucker, J. W.; Stephenson,
C. R. J. J. Org. Chem. 2012, 77, 1617. (e) Xuan, J.; Xiao, W.-J. Angew.
Chem., Int. Ed. 2012, 51, 6828. (f) Maity, S.; Zheng, N. Synlett 2012, 23,
1851.
(10) (a) Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2009, 131, 10875. (b) Nagib, D. A.; MacMillan, D. W. C.
Nature 2011, 480, 224. (c) Iqbal, N.; Choi, S.; Ko, E.; Cho, E. J.
Tetrahedron Lett. 2012, 53, 2005. (d) Ye, Y.; Sanford, M. S. J. Am.
Chem. Soc. 2012, 134, 9034. (e) Iqbal, N.; Choi, S.; Kim, E.; Cho, E. J.
J. Org. Chem. 2012, 77, 11383.
(11) (a) Koike, T.; Akita, M. Chem. Lett. 2009, 38, 166. (b) Yasu, Y.;
Koike, T.; Akita, M. Chem. Commun. 2012, 48, 5355. (c) Yasu, Y.;
Koike, T.; Akita, M. Angew. Chem., Int. Ed. 2012, 51, 9567. (d) Koike,
T.; Yasu, Y.; Akita, M. Chem. Lett. 2012, 49, 999. (e) Yasu, Y.; Koike,
T.; Akita, M. Adv. Synth. Catal. 2012, 354, 3414. (f) Yasu, Y.; Koike, T.;
Akita, M. Chem. Commun. 2013, 49, 2037–2039.
(12) (a) Umemoto, T. Chem. Rev. 1996, 96, 1757 and references cited
therein. (b) Eisenberger, P.; Gischig, S.; Togni, A. Chem.;Eur. J. 2006,
12, 2579. (c) Kieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chem., Int.
Ed. 2007, 46, 754.
(13) (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045.
(b) Ritter, J. J.; Kalish, J. J. Am. Chem. Soc. 1948, 70, 4048.
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F. Top. Curr. Chem. 2007, 281, 143.
(16) 3n, 3t, and 3ae: Molecular structures are shown in the Support-
ing Information. CCDC 915838, CCDC 916965, and CCDC 921846
contain the supplementary crystallographic data. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(17) For recent reviews on the synthesis of trifluoromethylated amino
acids, see: (a) J. Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem. Rev.
2011, 111, 455. (b) Qiu, X.-L.; Qing, F.-L. Eur. J. Org. Chem. 2011, 3261.
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Org. Lett., Vol. 15, No. 9, 2013
2137

yields). Finally, this difunctionalization protocol was also
compatible with nitrile functionality and the correspond-
ing product 3p was obtained in 89% yield. These results
indicate that the present photocatalytic aminotrifluoro-
methylation leads to the efficient and regioselective reac-
tions for styrenes bearing a variety of functional groups.
Table 2. Scope of the Present Photocatalytic
Aminotrifluoromethylation of Terminal Alkenesa
Scheme 2. Scope of Internal Alkenes
Scheme 3. Application to Late-Stage Aminotrifluoromethylation
of Steroid and Amino Acid Scaffolds
a The reaction was carried out under N2 atmosphere and irradiation
of 425 nm blue LEDs at room temperature using [Ru(bpy)3](PF6)2 (1.25
μmol), 1a (0.25 mmol), vinylarene (1.1ꢀ6.0 equiv), MeCN (5.0 mL), and
H2O (1.0 equiv) in a 20 mL Schlenk tube. b 6.0 equiv of alkene was used.
c Irradiation time = 14 h. d 2,6-Lutidine (1.5 equiv) was used as additive.
absence of photocatalysts (entries 6 and 7), strongly sup-
porting that the photoexcited species of the photoredox
catalysts play key roles in the reaction.
The scope of the present photocatalytic aminotrifluor-
omethylation is summarized in Table 2. Styrenes with a
methyl substituent at the ortho (2b), meta (2c), or para (2d)
position smoothly produced the corresponding coupling
products 3bꢀd in excellent yields (91% yields) upon
irradiation for 3 h. In addition, this reaction could be
applied to styrenes bearing halogen atoms, F (2e), Cl (2f, j),
and Br (2g, i), and the aminotrifluoromethylated products
(3eꢀg, i and j) were obtained in high yields (83ꢀ89%
yields). Electron-withdrawing groups such as a trifluoro-
methyl group, CF3 (2h), an aldehyde group, CHO (2k),
and anester group, CO2Me(2l), didnothinderthereaction
(78ꢀ91% yields). It should be noted that the transforma-
tion is tolerated with a Boc-protected amino group,
NHBoc (2m), an acetoxy group, AcO (2n), and a boronic
acid ester, Bpin (2o), and the corresponding CF3-substituted
amides (3mꢀo)16 were obtained in good yields (75ꢀ81%
Next, to expand the scope, internal alkenes were exam-
ined (Scheme 2). The reactions of trans-β-methylstyrene
2q, indene 2r, and 1,2-dihydronaphthalene 2s regioselec-
tively provided the CF3-substituted amide products 3qꢀs
in good yields (71ꢀ87%) but with a moderate level of dia-
stereoselectivitiy. The reaction of trans-stilbene 2t showed
a high diastereoselectivity ((1R*, 2R*):(1R*, 2S*) = 89:11).
One of the diastereomers, (1R*,2R*)-3t, was determined by
X-ray crystallographic analysis (Figure S3, Supporting
Information).16 Remarkably, the cinnamic acid esters 2u
and 2v could be also used for this photocatalytic transfor-
mation. The reactions proceeded smoothly to give the R-
trifluoromethyl-β-amino acid derivatives 3u and 3v, which
are potentially bioactive substances,17 in good yields and
high regioselectivity. It should be noted that the present
photocatalytic reaction gave the aminotrifluoromethy-
lated products in a highly regioselective manner regardless
of the position of the double bond, i.e., terminal or
internal.18
(18) It was found that scope of the present transformation is limited
to vinylarenes and β-substituted styrenes (see the Supporting
Information).
(19) For selected examples, see: (a) Kuhl, A.; Kolkhof, P.; Erguden,
J.-K.; Pernerstofer, J.; Telan, L.; Peters, J.-G.; Castro-Palomino, J.;
Torrejon-Nieto, J.; Lustig, K.; Kast, R.; Munter, K.; Stasch, J.-P.; Tinel,
H.; Coulter, T. S.; Montalbetti, C. A. G. N.; Yarnold, C. J. PCT
International Patent Application GB 2404658, February 9, 2005. (b)
Brueggemeier, U.; Fuerstner, C.; Geiss, V.; Keldenich, J.; Kern, A.; Delbeck,
M.; Kolkhof, P.; Kretschmer, A.; Pook, E.; Schmeck, C.; Truebel, H. PCT
International Patent Application WO 2010/105770, September 23, 2010.
2138
Org. Lett., Vol. 15, No. 9, 2013

This facile method for simultaneous introduction of two
functional groups onto diverse CdC bonds might serve as
a new synthetic strategy to easily improve biological
activities of natural products or drugs. The reactions of
vinylestrone 2w and vinyl-N-benzoyl-L-tyrosine ethyl ester
2x smoothly proceeded to afford the corresponding CF3-
substituted amide products 3w and 3x in 56% and 76%
isolated yields, respectively (Scheme 3). These results show
that this photocatalytic system can be applicable to “late-
stage aminotrifluoromethylation” of complex small mole-
cules such as steroids and amino acids.
photocatalyst. As a result, the product 3a was isolated in
84% yield (1.14 g). Subsequent deprotection of the acetyl
group furnishedthe ammonium salt, whichisan important
intermediate for a treatment agent of cardiovascular
disease,19a,b in 70% yield (see the Supporting Information).
This result suggests that we can easily access the corre-
sponding β-CF3-amines by the consecutive aminotrifluor-
omethylation and deprotection of the resultant acetylamide.
Furthermore, it was found that the present photocata-
lytic aminotrifluoromethylation can harness the ambient
sunlight as the light source. Sunlight induced the reaction
in a similar efficiency and selectivity to irradiation with
blue LEDs, even though the experiment was conducted
during the winter season in Japan (Supporting Information).
A plausible reaction mechanism via SET processes (oxi-
dative quenching) is shown in Scheme 5. First, irradiation
Scheme 4. Scope of Organic Nitriles
of visible light excites [Ru(bpy)3]2þ into *[Ru(bpy)3]2þ
Umemoto’s reagent 1a is reduced by *[Ru(bpy)3]2þ to
.
•
•
generate CF3. Addition of CF3 to alkene 2 gives the
radical intermediate, which is oxidized by [Ru(bpy)3]3þ
(path a) formed through the SET process. There is another
possible pathway, i.e., radical propagation (path b). Fi-
nally, the β-trifluoromethylated carbocation intermediate
is attacked by RCN, and the following hydrolysis (Ritter-
type amination) affords the aminotrifluoromethylated
product 3.
Scheme 5. Plausible Reaction Mechanism
In conclusion, we have developed the first intermolecu-
lar aminotrifluoromethylation of alkenes using visible-
light-driven photoredox catalyst [Ru(bpy)3](PF6)2. This
highly efficient and regioselective difunctionalization pro-
tocol enables practical one-step access to a variety of
β-trifluoromethylamides bearing many functional groups
under mild conditions. Furthermore, this photocatalytic
reaction proves “late-stage aminotrifluoromethylation” of
steroid and amino acid scaffolds. Further development
directed to synthesis of CF3-containing biologically active
compounds is a continuing effort in our laboratory.
As shown in Scheme 3, when CH2Cl2 was added to the
reactions of 2w and 2x to dissolve them, aminotrifluoro-
methylation proceeded readily in the same way. These
results indicate that the present reaction does not need to
use organic nitrile as the solvent. Thus, we examined other
organic nitriles as N-nucleophiles in the mixed solvent
system. The reactions in mixtures of organic nitriles and
CH2Cl2 (1:9) afforded the corresponding amides, propio-
namide 3aa, 2-(methoxy)ethylamide 3ab, isobutyramide 3ac,
cyclopropanecarboxamide 3ad, and cyclohexylcarboxamide
3ae16 in moderate to good yields (53ꢀ77%) (Scheme 4).
As a demonstration of scalability of the present photo-
catalytic reaction, the aminotrifluoromethylation of 2a
was carried out on a gram scale using 0.3 mol % of
Acknowledgment. This work was supported by a
grants-in-aid from the Ministry of Education, Culture,
Sports, Science of the Japanese Government (Nos.
23750174, 22350024 and 24108101) and the global COE
program (the GCOE) “Education and Research Center for
Emergence of New Molecular Chemistry”
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 9, 2013
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