Direct aromatic C-H trifluoromethylation via an electron-donor-acceptor complex

Article abstract of DOI:10.1002/chem.201500896

A novel electron-donor-acceptor (EDA) complex-mediated direct C-H trifluoromethylation of arenes with Umemoto's reagent has been developed. This transformation has been enabled by an unprecedented EDA complex formed by Umemoto's reagent and an amine, whic

Full text of DOI:10.1002/chem.201500896

DOI: 10.1002/chem.201500896
Communication
&
CÀH Functionalization
Direct Aromatic CÀH Trifluoromethylation via an Electron-Donor–
Acceptor Complex
Yuanzheng Cheng,[a] Xiangai Yuan,[b] Jing Ma,*[b] and Shouyun Yu*[a]
CF3 radical species.[7–10] There are three major ways to generate
C
Abstract: A novel electron-donor–acceptor (EDA) com-
plex-mediated direct CÀH trifluoromethylation of arenes
with Umemoto’s reagent has been developed. This trans-
formation has been enabled by an unprecedented EDA
complex formed by Umemoto’s reagent and an amine,
which was supported by experiments and theoretical cal-
culations. The radical-based methodology presented here
allows to access highly-functionalized trifluoromethyl
arenes in up to 81% chemical yield.
C
CF3 radical (Figure 1a): i) oxidation of nucleophilic trifluorome-
thylating reagents, such as TMSCF3,[8a–c] Langlois’s reagent
(CF3SO2Na)[8d–f] and (CF3SO2)2Zn;[8g–h] ii) reduction of electrophilic
trifluoromethylating reagents, such as CF3SO2Cl,[9a–b] Umemo-
to’s reagent,[9c–h] Togni’s reagent[9i–l] and CF3I;[9m–o] iii) homolysis
or mesolysis of trifluoromethyl halides.[10] Recently, Melchiorre
group reported photochemical aromatic perfluoroalkylation
driven by the photochemically activated EDA complexes.[4b]
C
Despite these great advances, generation of CF3 radical
through an EDA complex is rare.[11]
Electron-donor–acceptor (EDA) complexes, also called charge-
transfer (CT) complexes,[1] were introduced by Mulliken[2] to
define a new type of adducts. This new molecular aggregate,
generally associated with conspicuous color change and are
proved to absorb radiation in the visible region, can be gener-
ated by the molecular interactions between electron donors
and acceptors. Over the last six decades, the photophysical
properties of EDA complexes have been extensively studied.[1,3]
Although EDA complexes are considered as key intermediates
in some reactions, especially in single-electron transfer (SET)
events, their use in chemical synthesis is limited since electron
transfers from donors to acceptors in EDA complexes are fast
and reversible. Recently, some useful transformations, such as
asymmetric alkylation, perfluoroalkylation and arylation of aro-
matic compounds, have been achieved assisted by EDA com-
plexes.[4] These promising results imply that EDA complexes
may find more applications in organic synthesis.
Introducing fluorine-containing functional groups into the
molecular scaffold of organic compounds greatly alters their
intrinsic properties.[5] It is not surprising that tremendous ad-
vances have been achieved in direct CÀH trifluoromethylation
of arenes.[6] Radical-based trifluoromethylation has received in-
creasing attention because direct CÀH trifluoromethylation
could be realized relatively under mild conditions using active
Figure 1. Radical trifluoromethylation.
It is known that tertiary amines are able to form EDA com-
plexes with electron-accepting molecules, which can facilitate
SET events.[12] We envisage that electron-deficient Umemoto’s
reagent (2) can serve as an electron acceptor to form an EDA
complex with a tertiary amine. Thus, we propose a radical
C(sp2)ÀH trifluoromethylation by taking advantage of this EDA
complex. As shown in Figure 1b, the lone pair of a tertiary
amine can engage in an EDA complex (I) with 2. The reduced
Umemoto’s reagent generated from electron transfer of the
[a] Y. Cheng, Prof. Dr. S. Yu
State Key Laboratory of Analytical Chemistry for Life Science
School of Chemistry and Chemical Engineering, Nanjing University
Nanjing 210093 (P. R. China)
E-mail: yushouyun@nju.edu.cn
[b] X. Yuan, Prof. Dr. J. Ma
C
C
EDA complex can collapse into CF3 radical irreversibly. The CF3
Institute of Theoretical and Computational Chemistry, School of Chemistry
and Chemical Engineering, Nanjing University, Nanjing 210093 (P. R. China)
E-mail: majing@nju.edu.cn
radical is then added onto an arene (1) to give a radical inter-
mediate II. The radical II is oxidized to cation III. After deproto-
nation, trifluoromethylated arenes is produced. This EDA com-
plex-mediated process could render direct CÀH trifluoromethy-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500896.
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lation of arenes without a directing group and transition-metal
catalyst under mild conditions.
3b, 3j vs 3k) without affecting this transformation significant-
ly. C3 Substitution had a positive effect on this reaction and
C3-free indoles gave lower yields (40% for 3m and 43% for
3n). Pyrrole derivatives could also go through this trifluorome-
thylation frequently without protecting nitrogen atom. Di-, tri-,
tetrasubstituted trifluoromethylated pyrroles 3o–3u were pro-
duced in up to 81% yield. 2-Trifluoromethylated benzofurans
3v (43% yield) and 3w (78% yield) could also be prepared by
means of this method. Electron-rich benzenes, such as 1,3,5-tri-
methoxybenzene and hydroquinone, were suitable substrates.
The desired products were isolated in acceptable yields (51%
for 3x and 50% for 3y). Cyclic enamides could also be trifluor-
omethylated to give 3a and 3aa with 51 and 70%, yield, re-
spectively. Attempts to trifluoromethylation of electron-neutral
and deficient benzenes, as well as pyridine derivatives, failed.
Our rationale was evaluated by selecting tryptamine deriva-
tive 1a and Umemoto’s reagent 2 as reaction partners. To our
delight, the trifluoromethylated product 3a was obtained in
63% yield based on 19F NMR analysis when a solution of 1a
and 2 in DMF was treated with trimethylamine (TEA) at room
temperature for 18 h (Table 1, entry 1). This result prompted us
to investigate a series of secondary and tertiary amines. All the
amines we tested could promote this transformation to give
3a with 45–73% NMR yield (entries 2–11). N-Methylmorpholine
(NMM) was superior to other amines with 73% NMR yield
(64% isolated yield) (entry 4). Solvents were also examined.
However, none of them gave improved results (entries 12–18).
Oxygen had no obvious effect on this transformation
(entry 19).
Table 2. Substrate Scope and limitation of trifluoromethylation.[a,b]
Table 1. Reaction condition optimization.[a]
Entry
Organic base
Solvent
Yield[b] [%]
1
2
3
4
5
6
7
8
Et3N
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
NMP
DMSO
MeOH
MeCN
THF
63
45
63
73 (64[c])
71
72
63
61
53
59
57
61
64
64
31
53
46
50
72
iPr2NEt
TMEDA
NMM
morpholine
DMEDA
iPr2NH
dibenzylamine
piperidine
pyrrolidine
Et2NH
NMM
NMM
NMM
NMM
NMM
NMM
NMM
NMM
9
10
11
12
13
14
15
16
17
18
19[d]
DCM
DMF
[a] Reaction conditions: A solution of 1a (0.1 mmol), 2 (0.2 mmol) and
amine (0.2 mmol) in the indicated solvent (1.0 mL) was stirred at room
temperature for 18 h. [b] Determined by 19F NMR with PhCF3 as the inter-
nal standard. [c] Isolated yield. [d] Under N2 using degassed solvent.
TMEDA=N,N,N’,N’-Tetramethylethylenediamine, NMM=4-methylmorpho-
line, DMEDA=N,N’-dimethyl-1,2-ethanediamine.
With establishing this simple and efficient trifluoromethyla-
tion protocol, we proceeded to explore the scope and limita-
tions of this transformation (Table 2). Firstly, various indole de-
rivatives were examined, including biologically important trypt-
amine, tryptophan and melatonin derivatives. We were pleased
to find that all the indole derivatives could undergo this reac-
tion smoothly to give desired product 3a–3n in 43–75% iso-
lated yield. The N1 position could be free or protected (3a vs
[a] Reaction conditions: A solution of 1 (0.2 mmol), 2 (0.4 mmol) and
NMM (0.4 mmol) in DMF (1.0 mL) was stirred at room temperature.
[b] Isolated yield. [c] Determined by 19F NMR with PhCF3 as the internal
standard.
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In order to gain some insights into the mechanism of this re-
action, a series of control experiments were carried out
(Scheme 1). As shown in Scheme 1a, this transformation could
be terminated completely by introducing TEMPO. No desired
C
product 3a was observed, and CF3 radical trapping product 3
was obtained instead in 3.3% yield based on 19F NMR analysis,
which implied the radical nature of this reaction. When the re-
action was carried out in dark, the desired product 3a could
be generated in 71% yield, which showed that the light did
not affect this transformation. When the loading of NMM was
reduced to 0.1 equivalents, 3a could be obtained in 23% yield,
which suggested that NMM was served as an initiator or could
be regenerated. In the absence of NMM, the starting material
1a was fully recovered (Scheme 1b).
Figure 2. X-band EPR spectrum obtained in DMF at 298 K in the presence of
PBN. Line I: A solution of 1a (0.1 mmol), 2 (0.2 mmol), NMM (0.2 mmol), PBN
(0.2 mmol) in DMF (1 mL). Line II: A solution of 1a (0.1 mmol), 2 (0.2 mmol),
PBN (0.2 mmol) in DMF (1 mL). Line III: A solution of PBN in DMF (1 mL).
Scheme 1. Control experiments. The yield and conversions were determined
Based on our experimental observations, a possible mecha-
nism is proposed for this transformation (Figure 4). In contrast
to recent examples where the photo-activity of EDA complexes
is responsible,[4a–d] the reversible electron transfer (ET) in the
EDA complex 5 is activated thermally and lead collapse of 5
by 19F NMR with PhCF3 as the internal standard.
C
The CF3 radical could be observed using electron paramag-
netic resonance (EPR) in the presence of a spin trap tert-butyl-
a-phenylnitrone (PBN) (Figure 2). When PBN was added into
the reaction mixture under the standard conditions, a spectrum
at g=2.00646 (298 K) was recorded that could be clearly
traced to the CF3-PBN spin trap.[13]
into CF3 radical and NMM+ irreversibly.[4f–h,19] The CF3 radical
C
C
C
is then added onto arene 1a to give radical 7. Radical 7 is oxi-
C
dized by radical cation NMM+ to generate cation 8 and re-
generate NMM (path A). Ultimately deprotonation of cation 8
assisted by NMM yields the final product 3a. At this stage, oxi-
dation of 7 to 8 by Umemoto’s reagent 2 cannot be ruled out
completely (path B).
Given the weak reductive capacity of NMM (ENMM/NMM+
=
C
1.2 V vs SCE)[14] and oxidative capacity of Umemoto’s reagent 2
(E2/2 À =À0.35 V vs SCE),[15] intermolecular SET from NMM to 2
In summary, we have described originally a simple and effi-
cient method for direct CÀH trifluoromethylation of arenes
with Umemoto’s reagent. The CF3 radical is generated by an
EDA complex formed by Umomoto’s reagent and an amine,
a novel medium which is different from the reported methods.
Some experiments and theoretical calculations were furnished
to support the EDA complex. Transition-metal catalysts, direct-
ing groups and external oxidants can be avoided. The method-
ology presented here allows to access highly-functionalized
CF3-containing indoles, pyrroles, benzofurans and electron-rich
benzenes at room temperature in good chemical yields. Fur-
ther application using this EDA complex, as well as more de-
tailed mechanism investigation, are underway in our laborato-
ry.
C
is thermodynamically disfavored. It is known that tertiary
amines are able to form EDA complexes with electron-accept-
ing molecules, so this SET event can be facilitated by an EDA
complex of 2 with NMM (Figure 3a).[12] The existence of the
1
EDA complex could be supported by the H NMR spectroscopy
and UV/VIS spectrum.[1h,16] Using Job’s method of continuous
variations, a molar donor/acceptor ratio of 1:1 in solution for
EDA was readily established.[17] Concomitantly the equilibrium
constants KEDA (KEDA =18.7) for formation of the EDA complex
were determined spectrophotometrically (using the Benesi–Hil-
debrand method).[18] Theoretical calculations showed that the
formation of the EDA complex was thermodynamically favored
(for details, see Supporting information) (Figure 3d). This band
is associated with an electron-transfer transition from HOMO
(H) to LUMO (L) of this complex. For details, see Supporting In-
formation). The formation of the EDA complex was further sup-
ported by NMR titration (Figure 3b). The appearance of a new
Experimental Section
A 3 mL nap vial was equipped magnetic stir bar and was charged
with a solution of arene or heteroarene 1 (0.2 mmol, 1.0 equiv),
1
set of signals in the H NMR spectroscopy of the mixture of
NMM and 2 provided proof of the EDA complex.
Umemoto’s reagent 2 (0.4 mmol, 2.0 equiv), NMM (0.4 mmol,
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ence Foundation of Jiangsu
Province (BK20131266) is ac-
knowledged.
Keywords: arenes
functionalization
acceptor systems
·
CÀH
donor–
electron
·
·
transfer · trifluoromethylation
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concentrated under reduced pressure after filtration. The crude
product was purified by flash chromatography on silica gel to
afford the desired product 3.
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Acknowledgements
Financial support from the 973 Program (2011CB808600), the
863 program (2013AA092903), the National Natural Science
Foundation of China (21472084, 21290192), the Natural Sci-
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[17] P. Job, Justus Liebigs Ann. Chem. 1928, 9, 113.
[18] H. Benesi, J. Hildebrand, J. Am. Chem. Soc. 1949, 71, 2703.
[19] For selected examples on EDA-thermal activation, see: a) T. Miyashi, M.
Kamata, T. Mukai, J. Am. Chem. Soc. 1987, 109, 2780; b) K. N. Houk, L. L.
Munchausen, J. Am. Chem. Soc. 1976, 98, 937; c) R. Noyori, N. Hayashi,
M. Kato, J. Am. Chem. Soc. 1971, 93, 4948.
[10] For selected examples, see: a) T. Xu, C. W. Cheung, X. Hu, Angew. Chem.
Int. Ed. 2014, 53, 4910; b) V. M. Labroo, R. B. Labroo, L. A. Cohen, Tetra-
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Received: March 6, 2015
Published online on && &&, 0000
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
CÀH Functionalization
Y. Cheng, X. Yuan, J. Ma,* S. Yu*
&& – &&
Direct Aromatic CÀH
Trifluoromethylation via an Electron-
Donor–Acceptor Complex
New complex in town: Direct CÀH tri-
fluoromethylation of arenes with Umo-
moto’s reagent is described. This strat-
egy is enabled by a novel electron-
donor–acceptor (EDA) complex formed
by Umomoto’s reagent and an amine.
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!