Hydrotrifluoromethylation of Unactivated Alkenes and Alkynes Enabled by an Electron-Donor-Acceptor Complex of Togni's Reagent with a Tertiary Amine

Article abstract of DOI:10.1021/acs.orglett.6b01301

An electron-donor-acceptor (EDA) complex between Togni's reagent and a tertiary amine has been introduced. The existence of this EDA complex was supported by NMR titration experiments. The hydrotrifluoromethylation of unactivated aliphatic alkenes and alkynes enabled by this EDA complex has also been developed. This hydrotrifluoromethylation protocol is operationally simple and promoted by a tertiary amine.

Full text of DOI:10.1021/acs.orglett.6b01301

Letter
pubs.acs.org/OrgLett
Hydrotrifluoromethylation of Unactivated Alkenes and Alkynes
Enabled by an Electron-Donor−Acceptor Complex of Togni’s
Reagent with a Tertiary Amine
Yuanzheng Cheng and Shouyun Yu*
State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210023, China
*
S Supporting Information
ABSTRACT: An electron-donor−acceptor (EDA) complex between
Togni’s reagent and a tertiary amine has been introduced. The existence
of this EDA complex was supported by NMR titration experiments. The
hydrotrifluoromethylation of unactivated aliphatic alkenes and alkynes
enabled by this EDA complex has also been developed. This hydrotrifluoro-
methylation protocol is operationally simple and promoted by a tertiary
amine.
Electron-donor−acceptor (EDA) complexes introduced by
1
Mulliken define a new type of noncovalent interaction. An
EDA complex is an association of two molecules, named an
2
electron donor and an electron acceptor. Although the
photophysical properties of EDA complexes have been
3
extensively studied, EDA complex-enabled chemical synthesis
remains largely unexplored because the electron transfer from
4
−6
the donor to the acceptor is fast and reversible.
Recently,
useful photochemical transformations, such as cycloaddition,
alkylation, and arylation of aromatic compounds, have been
5
achieved mediated by EDA complexes. Despite these
promising advances, EDA complex-enabled synthetic chemistry
is still in its infancy and in need of further investigated.
Very recently, our group reported a new type of EDA
complex using a tertiary amine as the electron donor and
7
Umemoto’s reagent as the electron acceptor. By taking
advantage of this EDA complex, a direct aromatic C−H
7
trifluoromethylation has been developed (Figure 1a). Inspired
by this work, we sought to apply the EDA complex to more
challenging reactions. Despite the fact that tremendous
achievements have been made in the trifluoromethylation of
different functional groups, the hydrotrifluoromethylation of
unactivated alkenes and alkynes is still synthetically challenging
Figure 1. Trifluoromethylation and hydrotrifluoromethylation enabled
by an EDA complex.
1
9
methylation product 3a was obtained in 64% yield based on F
10a,b
8
,9
NMR analysis when a solution of Umemoto’s reagent 1a
and 2a in DMF was treated with NMM at room temperature
and remains largely unexplored. Recently, Liu’s research
group reported the organic base-promoted radical trifluor-
omethylation of alkenes and related cascade reactions with
10c−e
for 24 h (entry 1). When we use Togni’s reagent 1b,
9
a,c
another typical electrophilic trifluoromethylating reagent, as an
electron acceptor, the yield slightly improved to 66% (entry 2).
However, no desired product was furnished when Togni’s
reagent 1c was used instead of 1b (entry 3). Other electron
Togni’s reagent. Despite these advances, the exploration of
alternative and mechanistically distinct systems is still
imperative. Herein, a strategy for hydrotrifluoromethylation of
unactivated aliphatic olefins and alkynes was proposed by
taking advantage of the EDA complex between an electrophilic
trifluoromethylating reagent and a tertiary amine (Figure 1b).
This rationale was then tested using alkene 2a as the model
substrate (Table 1). To our delight, the desired hydrotrifluoro-
donors, such as 1-methylpiperidine, Et N, piperidine, and i-
3
Received: May 4, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01301
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Letter
a
Table 1. Optimized Reaction Conditions
b
entry
solvent
DMF
amine
NMM
1
yield (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
64
66
0
DMF
NMM
DMF
NMM
DMF
N-Me-piperidine
63
51
58
28
57
62
64
DMF
Et N
3
DMF
piperidine
DMF
i-Pr NH
2
NMP
NMM
NMM
NMM
NMM
NMM
NMM
NMM
−
DMAc
Figure 2. Mechanistic investigations. (a) NMR titration. (b) KEDA for
formation of the EDA complex determined by NMR analysis. (c) Job’s
plot.
10
11
12
13
14
15
16
NMF
THF
36
c
pyrrolidin-2-one
pyrrolidin-2-one
pyrrolidin-2-one
pyrrolidin-2-one
pyrrolidin-2-one
80 (78 )
d
e
64
80
0
model reaction could be totally inhibited when TEMPO was
introduced into the reaction mixture. The radical nature of this
13
f
reaction was further confirmed by a radical clock experiment.
NMM
70
When a solution of Togni’s reagent (1b) and bisallyl
sulfonamide 4 was treated with NMM, cyclic sulfonamide 5
was generated through 5-exo-trig radical cyclization of radical 6
a
Reaction conditions: a solution of 2a (0.2 mmol), 1 (0.4 mmol) and
amine (0.4 mmol) in the indicated solvent (2.0 mL) was stirred at 25
b
19
°C for 24 h. Determined by F NMR with PhCF as the internal
3
c d e f
(Scheme 1). The CF · radical could be also observed using
standard. Isolated yield. Open to air. Degassed solvent was used. In
dark. NMM = 4-Methylmorpholine, NMP = 1-Methyl-2-pyrrolidi-
none, DMAc = N,N-Dimethylacetamide, NMF = N-Methylformamide.
3
Scheme 1. A Radical Clock Experiment
Pr NH, could not give improved results (entries 4−7). The
2
solvent effect was then examined (entries 4−12). Pyrrolidin-2-
one proved to be the optimal solvent with an 80% NMR yield
(
78% isolated yield) (entry 12). Oxygen could affect this
reaction slightly. The reaction carried out open to air resulted
in a 64% yield, while an 80% yield was obtained in the degassed
solvent under nitrogen (entries 13 and 14). The electron donor
was crucial to this transformation and no product was observed
in the absence of the tertiary amine (entry 15). When the
reaction was carried out in the dark, a slightly lower yield (70%)
was obtained (entry 16). This phenomenon suggests that the
EDA complex is activated thermally.
Given that an EDA complex can be formed between an
amine and Umemoto’s reagent 1a, we believe that the
electron paramagnetic resonance (EPR) in the presence of a
spin trap, tert-butyl-α-phenylnitrone (PBN) (for details, see
7
14
formation of an EDA complex between Togni’s reagent 1b and
an amine is also possible. To our delight, the encounter
complex I could be generated when NMM was selected as the
the Supporting Information).
We next tried to determine the source of hydrogen with the
assistance of deuteration experiments (Scheme 2). Hydro-
trifluoromethylation of alkene 2a with Togni’s reagent 1b
1
electron donor. The H NMR signals for the mixture of Togni’s
reagent 1b with NMM shifted downfield when the ratio of
Togni’s reagent 1b to NMM increased (Figure 2a).
Concomitantly, the equilibrium constant KEDA (KEDA = 3.83)
for the formation of the EDA complex was determined by
proceeded smoothly (58% yield) in DMF using n-Bu N as the
electron donor. When the reaction mixture was treated with
3
deuterated amine (n-Bu N-d ), no deuterated product was
3
27
observed. When the reaction was run in deuterated solvent
11
NMR analysis (using Foster’s method) (Figure 2b). The 1:1
(DMF-d ), 20% of the product was deuterated. When we used
7
molar ratio for the donor and acceptor was readily established
using Job’s method of continuous variations (Figure 2c).
In order to gain further insight into the mechanism of this
reaction, a series of control experiments were performed. The
deuterated amine (n-Bu N-d ) and solvent (DMF-d ), the
3
27
7
12
yield of the desired product decreased to 15%, and 37% of the
product was deuterated. These results implied that the solvent
served as the major hydrogen source.
B
DOI: 10.1021/acs.orglett.6b01301
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Letter
Scheme 2. Deuteration Experiments
Based on these observations, a rationale for this hydro-
trifluoromethylation is posited, as depicted in Scheme 3. An
Scheme 3. Rationale for EDA Complex-Mediated
Hydrotrifluoromethylation of Alkenes
encounter complex I can be generated when NMM is mixed
with Togni’s reagent 1b. The EDA complex I can be thermally
activated to the excited state, which dissociates into the CF ·
3
+
•
radical, acyl anion, and radical cation NMM . The CF · radical
3
is then captured by an unactivated alkene (2) to give an alkyl
radical intermediate II, which finally gives the desired
hydrotrifluoromethylation product after abstracting a hydrogen
atom from the solvent.
With the establishment of this simple and efficient
hydrotrifluoromethylation protocol, we proceeded to explore
the scope and limitations of this transformation. It was found
that a variety of terminal alkenes can be transformed into the
corresponding hydrotrifluoromethylation products in moderate
to good yields (Figure 3a). The mild reaction conditions
allowed for high functional group compatibility. A wide array of
functional groups, including amide, ester, heterocycle, ether,
sulfonamide, silicon ether, and alcohol, were well tolerated
Figure 3. Substrate Scope. Reaction conditions: a solution of 2 or 8
(0.2 mmol), 1b (0.4 mmol), and NMM (0.4 mmol) in pyrrolidin-2-
one (2.0 mL) was stirred at 25 °C for 24−72 h. Isolated yield. The E/
a
Z ratios were determined by NMR analysis. The reaction was run in
b
5
mmol scale. The yield was based on the recovered starting material.
through this transformation fluently to produce trifluoromethy-
lated alkenes 9a−9f in moderate to good yields (40−68%) as
mixtures of E/Z isomers. In all cases, the E-isomers were
isolated as the major stereoisomers. These reactions were
sluggish and could not go to completion in reasonable time.
The yields were quantitative based on the recovered starting
materials. The aromatic alkenes and alkynes were not suitable
substrates in this transformation and fully recovered under
standard conditions.
In summary, an operationally simple and efficient method for
hydrotrifluoromethylation of aliphatic alkenes and alkynes
enabled by an EDA complex has been developed. The existence
of this EDA complex between Togni’s reagent 1b and an amine
was supported by NMR titration experiments. The radical clock
experiment and electron paramagnetic resonance (EPR)
revealed the radical nature of this reaction. The only promoter
for this protocol is a tertiary amine. A series of trifluoromethy-
(3a−l). It was remarkable that biologically important natural
products or their derivatives could also go through this
transformation. For example, quinine was readily hydro-
trifluoromethylated to give 3n in 84% yield. Phenylalanine
and estrone derivatives proceeded smoothly to give the
corresponding hydrotrifluoromethylated products 3m (67%
yield) and 3o (61% yield) respectively. In order to demonstrate
the practicability of this transformation, 5 mmol of alkene 2a
were subjected to the standard conditions to furnish 3a in 73%
isolated yield (1.04 g).
The success in the hydrotrifluoromethylation of alkenes
inspired us to explore the possibility of hydrotrifluoro-
methylation of alkynes using this EDA complex-based strategy.
It was pleasing to find that alkynes could be also hydro-
trifluoromethylated under our established standard conditions
(Figure 3b). Functionalized terminal alkynes 8a−8f went
C
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Letter
lated aliphatic alkanes and alkenes with various functionalities
can be prepared using this method. Further studies on synthetic
application and to gain a better understanding of EDA
complexes are underway in our laboratory.
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ASSOCIATED CONTENT
Supporting Information
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Int. Ed. 2012, 51, 5048. (j) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01301.
(
9) (a) Yang, N. Y.; Li, Z. L.; Ye, L.; Tan, B.; Liu, X. Y. Chem.
Commun. 2016, DOI: 10.1039/C6CC00364H. (b) Zhu, L.; Wang, L.
S.; Li, B.; Fu, B.; Zhang, C. P.; Li, W. Chem. Commun. 2016, 52, 6371.
Experimental procedures and spectral data (PDF)
(c) Yu, P.; Zheng, S. C.; Yang, N. Y.; Tan, B.; Liu, X. Y. Angew. Chem.,
Int. Ed. 2015, 54, 4041. (d) Egami, H.; Usui, Y.; Kawamura, S.;
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AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: yushouyun@nju.edu.cn.
Notes
The authors declare no competing financial interest.
(i) Choi, S.; Kim, Y. J.; Kim, S. M.; Yang, J. W.; Kim, S. W.; Cho, E. J.
Nat. Commun. 2014, 5, 4881. (j) Ma, G.; Wan, W.; Li, J.; Hu, Q.; Jiang,
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(k) Mizuta, S.; Verhoog, S.; Engle, K. M.; Khotavivattana, T.; O’Duill,
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (21472084 and 81421091) and the
Qing Lan Project of Jiangsu Province is acknowledged.
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