NMP and O2 as Radical Initiator: Trifluoromethylation of Alkenes to Tertiary β-Trifluoromethyl Alcohols at Room Temperature

Article abstract of DOI:10.1021/acs.orglett.5b03035

A novel strategy was developed to trigger ·CF₃ by using in situ generated peroxide in NMP under O₂ or air as the radical initiator. Radical trifluoromethylation of alkenes was achieved toward tertiary β-trifluoromethyl alcohols. Various tertiary β-trifluoromethyl alcohols can be synthesized in good yields without extra oxidants or transition metal catalysts. Preliminary mechanistic investigation revealed that O₂ diffusion can influence the reaction rate.

Full text of DOI:10.1021/acs.orglett.5b03035

Letter
pubs.acs.org/OrgLett
NMP and O2 as Radical Initiator: Trifluoromethylation of Alkenes to
Tertiary β‑Trifluoromethyl Alcohols at Room Temperature
Chao Liu,† Qingquan Lu,† Zhiyuan Huang,† Jian Zhang,† Fan Liao,§ Pan Peng,† and Aiwen Lei*,†,‡
†College of Chemistry and Molecular Sciences, the Institute for Advanced Studies (IAS), Wuhan University, Wuhan, Hubei 430072,
P. R. China
‡State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Lanzhou 730000, P. R.
China
§National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, Jiangxi, P. R. China
S
* Supporting Information
ABSTRACT: A novel strategy was developed to trigger ·CF3 by using in situ
generated peroxide in NMP under O2 or air as the radical initiator. Radical
trifluoromethylation of alkenes was achieved toward tertiary β-trifluoromethyl
alcohols. Various tertiary β-trifluoromethyl alcohols can be synthesized in good
yields without extra oxidants or transition metal catalysts. Preliminary mechanistic
investigation revealed that O2 diffusion can influence the reaction rate.
ree radicals have attracted extensive attention in organic
choice. As an inexpensive, stable, easily handled, and stored
Fsynthesis, due to the presence of an unpaired electron that trifluoromethylation reagent, CF3SO2Na has been extensively
makes them highly reactive.1 As an important research point of
studied since the pioneering work by Langlois and co-workers
in 1991.6 In many previous reports, CF3SO2Na can be oxidized
radical chemistry, the generation of radical species has been
to CF3SO2· by many different oxidants, such as tert-butyl
studied continuously. To date, transition metal catalysts,
stoichiometric amount of oxidants, and organometallic reagents
have been the most widely applied methodologies to initiate
radicals.2 Solely using molecular oxygen to initiate some highly
active precursors to radicals has also been developed in recent
years.3 However, it is always valuable to seek general and
environmentally friendly methods to update these existing
achievements.
hydroperoxide (TBHP), PhI(OAc)2, etc.,7 and then CF3SO2·
8
can easily decompose to ·CF3 with the release of SO2. Those
results inspired us to make use of the low-concentration
peroxides in solvents by using CF3SO2Na as the radical
acceptor. In this regard, we proposed a new strategy for the
generation of ·CF3 by utilizing NMP and O2 together as the
radical initiator (Scheme 1).
Peroxides have been demonstrated as one of the most
effective radical initiators.4 Nevertheless, the preparation of
peroxides is an energy consuming process, and handling of
concentrated peroxides is dangerous. Undoubtedly, if peroxides
could be produced in situ, more environmentally friendly
synthesis will be realized. It is well-known that peroxides widely
exist in solvents such as terahydrofuran (THF), N-methyl-2-
pyrrolidone (NMP), etc., under an O2 or air atmosphere.5
However, on one hand, these peroxides sometimes induce side
reactions; on the other hand, the extremely slow generation
process and low concentration make them hard to put into use.
They are usually regarded as useless, harmful, and hazardous.
Based on these conditions, in situ generated peroxides in
solvents have been seldom utilized. Thus, new strategies
making use of those undesirable and “harmful” peroxides would
be meaningful, which would also deepen our understanding of
radical initiators for both academic and industrial research.
To make the low-concentration in situ generated peroxides
in solvents valuable, a suitable radical acceptor which can
efficiently react with them might be the critical factor. We
envisioned CF3SO2Na (Langlois reagent) would be a good
Scheme 1. New Strategy to Generate ·CF3 by Utilizing NMP
and O2 as Radical Initiator
To evaluate the practicality of our design, we attempted to
use operando IR to monitor the conversions of CF3SO2Na in
NMP and other solvents under an O2 atmosphere. Indeed, in
NMP, CF3SO2Na was gradually consumed along with the
generation of CF3SO3Na, which was the oxidized product of
CF3SO2Na initiated by CF3SO2· under O2 or air.9 The reason
that the conversion of CF3SO2Na (51%) in NMP is bigger than
the generation of CF3SO3Na (18%) is possibly due to the
Received: October 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03035
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Letter
simultaneous desulfurization of CF3SO2· to ·CF3 (blue line in
more effective, several experiments were performed (for more
details, see SI). Initially, different reaction temperatures were
tested, and the results showed that room temperature gave the
best yield. Reaction at 45 °C gave a similar result as that at
room temperature, and higher temperatures did not work well.
Solvent screening revealed NMP was the best choice since
other solvents, such as toluene, resulted in no desired product.
Finally, an excellent yield of 82% was obtained when the
volume of NMP decreased from 2 to 1 mL. Further reducing
the volume of NMP did not give a better result. Notably, no
desired product could be detected when the reaction was
carried out under a N2 atmosphere, indicating that O2 plays a
vital role in this transformation.
Mechanistic investigations were performed to understand
this highly selective transformation. As proposed in Scheme 1,
the in situ generated hydroperoxide from the reaction of NMP
and O2 might be the key intermediate for initiating the ·CF3,
itself decomposing to N-methylsuccinimide (4aa) eventually.
To verify our hypothesis, an 18O2 labeling experiment of model
reaction was conducted. Since the hydroperoxide was formed
with the participation of O2, 18O-labeled hydroperoxide or 4aa
should be detected. As expected, 18O-labeled 4aa′ was obtained
in 16% yield and in 90% isotopic purity (Scheme 2; see SI for
more details). Hence, hydroperoxide might be produced and
work as the vital intermediate for initiating ·CF3.
Figure 1). While use of other solvents, such as dimethylforma-
Figure 1. Kinetic profile of the reaction of CF3SO2Na (0.6 mmol) at
25 °C for 2 h in different solvents (4.0 mL) under 1 atm of O2
(balloon). (A) The concentration of CF3SO2Na in different solvents.
(B) The concentration of generated CF3SO3Na in different solvents.
mide (DMF) or ethyl acetate (EtOAc), resulted in no obvious
consumption of CF3SO2Na and no obvious generation of
CF3SO3Na (Figure 1). Additionally, no reaction occurred when
conducting this experiment under a N2 atmosphere in NMP
(see Supporting Information (SI) for more details). These
results indicated that the combination of NMP and O2 are
essential for facilitating the consumption of CF3SO2Na, which
is consistent with our design in Scheme 1.
Based on the above IR experiment, we speculated that ·CF3
might be generated upon mixing CF3SO2Na, NMP, and O2
together. To verify our speculation, alkenes and alkynes were
employed as radical acceptors to capture the ·CF3. As shown in
Table 1, the trifluoromethylation product was obtained in 53%
a
Scheme 2. Labeling Experiment of Model Reaction
a
Table 1. Tested Acceptors for the Capture of ·CF3
a
Reaction was carried out using 1a (0.2 mmol), 2 (0.6 mmol), and
NMP (1.0 mL) at 25 °C for 2 h under 18O2 atmosphere. Yield of 3aa
was determined by 19F NMR spectroscopy. Yield of 4aa was
determined by GC analysis.
Meanwhile, the model reaction under an 18O2 atmosphere
provides further chance to probe the vital role of O2. As shown
in Scheme 2, the 18O-isotopologue 3aa′ was obtained in 85%
yield and in 92% isotopic purity. This result revealed that O2
also acted as a reaction participant and was transferred into the
final product. This is the first report of highly selective synthesis
toward β-trifluoromethyl alcohols through the oxygenation
process.10
It is well-known that the reaction between NMP and O2
toward peroxide formation is slow at room temperature.
Therefore, we conjectured that the concentration of O2 should
affect the reaction rate. In this regard, the kinetic behavior of O2
was investigated by studying the reaction between 1a and 2. As
shown in Figure 2, the reaction rate decreased by decreasing
the concentration of O2 or by slowing down the stirring rate
under O2 in NMP. These results fit well with our hypothesis,
suggesting that O2 diffusion can influence the reaction rate.
Additionally, the model reaction between 1a and 2 was also
monitored by operando IR. Compared with the blank reaction
in the absence of 1a, the conversion of 2 in the model reaction
was faster than the one in the blank reaction (Figure 3), and the
final conversions were 66% versus 51%. This result showed that
1a accelerates the consumption of 2, presumably because the
alkene shifts the reaction equilibrium to accelerate the
evolution of SO2 by trapping the generated ·CF3.
a
All reactions were carried out using alkene or alkyne (0.2 mmol),
CF3SO2Na (0.6 mmol), and NMP (2.0 mL) under an O2 atmosphere
at 25 °C for 2 h. Yields were determined by 19F NMR spectroscopy
using PhCF3 as internal standard. N.D. = not detected.
yield when α-methylstyrene was used. In contrast, α-
bromostyrene could only provide 8% trifluoromethylation
product, and trace or no corresponding product could be
observed when phenylacetylene or chalcone was employed.
These results not only elucidated the generation of ·CF3 but
also suggested that the electrophilic ·CF3 was more apt to add
to electron-rich unsaturated compounds.
The above kinetic investigations and ·CF3 capture experi-
ments concluded that the combination of NMP and O2 could
be a novel initiation strategy for radicals. However, as described
in Table 1, when this new radical initiation strategy was utilized
in the synthesis of 4,4,4-trifluoro-2-phenyl-2-butanol (3aa)
from α-methylstyrene (1a) and CF3SO2Na (2), only a
moderate yield was obtained. To make this new strategy
B
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Scheme 4. A series of α-substituted styrenes, such as ethyl,
cyclopropyl, phenyl substituted styrenes and 1-phenyl-1-
Scheme 4. Substrate Scope of Trifluoromethylation of
a
Alkenes
Figure 2. Kinetic profile of the reaction of 1a (0.2 mmol), 2 (0.6
mmol) at 25 °C for 2 h in NMP (4.0 mL) under different conditions.
(A) The concentration of CF3SO2Na at different O2 concentrations.
(B) The concentration of generated CF3SO2Na at different stirring
rates.
Figure 3. Concentration of CF3SO2Na under two different conditions.
Red line: 1a (0.2 mmol) and 2 (0.6 mmol) in NMP (4.0 mL) at 25 °C
for 2 h under 1 atm of O2 (balloon). Black line: 2 (0.6 mmol) in NMP
(4.0 mL) at 25 °C for 2 h under 1 atm of O2 (balloon).
Based on the previous reports and the above-mentioned
results, a tentative mechanism was proposed in Scheme 3.
Scheme 3. Tentative Reaction Mechanism
a
Unless otherwise specified, all reactions were carried out using 1 (0.2
mmol), 2 (0.6 mmol), and NMP (1.0 mL) under different conditions.
Yields are determined by 19F NMR spectroscopy, and yields of isolated
b
products are shown in parentheses after PPh3 worked. 1.0 mmol of
CF3SO2Na, 2 mL of NMP for 12 h.
cyclohexene, afforded the desired products in moderate to
excellent yields (3aa−3ae). α-Methylstyrene derivatives bearing
either electron-withdrawing or -donating groups on the aryl
ring provided the corresponding products 3af−3ap in good to
excellent yields. A range of functional groups including OMe
(3ah and 3ai), halogens (3al−3ao), and CF3 substituents
(3ap) were demonstrated to be well tolerated in this
transformation. Notably, a thiophenyl substituent, which is
easily overoxidized in oxidative conditions, was well tolerated in
this method, giving the corresponding product 3ak in 67%
yield. The heteroaryl substrate, 2-(prop-1-en-2-yl)thiophene,
was also well-behaved to give the expected product 3aq in 36%
yield. Notably, nonconjugated olefin, such as benzyl meth-
acrylate, was suitable for this protocol, giving the desired
product 3ar in 34% yield.
In conclusion, we have developed a novel strategy combining
NMP and O2 as the radical initiator to activate CF3SO2Na. By
using this novel strategy, an aerobic radical trifluoromethylation
of alkenes to tertiary β-trifluoromethyl alcohols was achieved.
This protocol exhibits a broad substrate scope for the synthesis
of various valuable β-trifluoromethyl alcohols at room temper-
ature without extra oxidants or transition metal catalysts.
NMP reacted with O2 to generate the hydroperoxide
intermediate, which serves as a radical initiator to oxidize
CF3SO2Na to CF3SO2· (I), itself decomposing to N-
methylsuccinimide (4aa) eventually. The radical I could react
with O2 toward the formation of CF3SO3Na or decompose to ·
CF3 (II) with the evolution of SO2. The resulting II adds to 1a
to afford the carbon-centered radical intermediate III, which
would be further captured by O2 and transformed into peroxide
radical IV. This newly formed O-centered radical could also
serve as an electron acceptor from 2 via a single electron
oxidation process to intermediate V with the regeneration of
I.11 Finally, the desired product 3aa could be achieved after the
hydrogen abstraction process and reduced either by 2 or by the
extraneous reductant.
With an understanding of this NMP and O2 initiated radical
trifluoromethylation reaction, the generality of this trans-
formation was evaluated, and the results are summarized in
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03035.
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The experimental procedure, characterization data, and
1
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: aiwenlei@whu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the 973 Program
(2012CB725302), the National Natural Science Foundation
of China (21390400, 21520102003, 21272180, and 21302148),
the Hubei Province Natural Science Foundation of China
(2013CFA081), the Research Fund for the Doctoral Program
of Higher Education of China (20120141130002), and the
Ministry of Science and Technology of China
(2012YQ120060). The Program of Introducing Talents of
Discipline to Universities of China (111 Program) is also
appreciated.
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