Iodotrifluoromethylation of alkenes and alkynes with sodium trifluoromethanesulfinate and iodine pentoxide

Article abstract of DOI:10.1021/ol501380e

A scalable, selective, and operationally easy iodotrifluoromethylation of a wide range of alkenes and alkynes by using two simple and safe solids, sodium trifluoromethanesulfinate and iodine pentoxide, in aqueous medium has been developed. Mechanistic studies confirm that free-radical processes are involved in this system since the key radical intermediates such as CF₃ and β-CF₃ alkyl radicals have been clearly detected by spin trapping and electron spin resonance.

Full text of DOI:10.1021/ol501380e

Letter
pubs.acs.org/OrgLett
Iodotrifluoromethylation of Alkenes and Alkynes with Sodium
Trifluoromethanesulfinate and Iodine Pentoxide
Zhaojia Hang, Zejiang Li, and Zhong-Quan Liu*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, China
S
* Supporting Information
ABSTRACT: A scalable, selective, and operationally easy
iodotrifluoromethylation of a wide range of alkenes and
alkynes by using two simple and safe solids, sodium
trifluoromethanesulfinate and iodine pentoxide, in aqueous
medium has been developed. Mechanistic studies confirm that
free-radical processes are involved in this system since the key
radical intermediates such as CF3 and β-CF3 alkyl radicals have
been clearly detected by spin trapping and electron spin
resonance.
variety of billion dollar pharmaceuticals, agrochemicals,
Scheme 1. Strategies for Iodotrifluoromethylation of Alkenes
A
and materials contain a trifluoromethyl (CF3) group
and Alkynes
mainly because the electron-withdrawing nature, unique
lipophilicity, and metabolic stability of this special substituent
can dramatically modify their properties.1 Hence, much effort
has been made to explore new efficient strategies for
introduction of the CF3 group into organic molecules in the
past decades.2−4 Recently, strategies for difunctionalization-
type trifluoromethylation of alkenes and alkynes have drawn
considerable attention due to the convenient and versatile
further functional group transformations of the products. For
example, a wide range of CF3-bearing building blocks such as
carbocycles, aziridines, epoxides, and lactones can be easily
prepared via the carbotrifluoromethylation,5 aminotrifluoro-
methylation,6 and oxytrifluoromethylation7 of alkenes. Among
these trifluoromethylation-involved difunctionalization of un-
saturated bonds, halotrifluoromethylation, especially the iodo-
trifluoromethylation of olefins and alkynes, has attracted much
attention in the past years.8 Given the well-known nucleophilic
substitution and cross-coupling importance and utility of
iodides, it is not surprising that chemists have made great
efforts to develop more efficient methods for incorporation of
iodine and the CF3 group into organic compounds in one step.
However, almost all of these strategies for direct iodotrifluoro-
methylation of alkenes and alkynes are achieved by using CF3I,
which is a gas and makes the operation hard to handle (Scheme
1). Therefore, more safe and operationally easy iodotrifluoro-
methylation of alkenes and alkynes is highly desirable.
methylation of arenes,9a heterocycles,9b,c aryl boronic acids,9d,e
and α,β-unsaturated acids.9g As our continuous studies on
single-electron-transfer reactions, we find that several inorganic
iodines such as iodic acid (HIO3, IA) and iodine pentoxide
(I2O5, IP) can act as safe and reliable single-electron oxidative
surrogates for organic hypervalent iodines in some cases.10
Although they are rarely used in organic synthesis,11 IA and IP
are extensively applied in industry due to their particular
stability and low-cost.12 Inspired by our previous work, we
envisioned whether IA/IP could promote a free-radical
iodotrifluoromethylation of alkenes and alkynes through
oxidation of CF3SO2Na. If it did work, it would provide a
novel and safe strategy for iodotrifluoromethylation of olefins
and alkynes without using gaseous CF3I. Fortunately, we
successfully accomplished a safe, green, and scalable method-
ology for iodotrifluoromethylation of a wide range of alkenes
and alkynes by using two simple, stable, and inexpensive solids
CF3SO2Na and I2O5 in aqueous medium (Scheme 1).
To solve the problems, we began to hypothesize that single-
electron oxidation of a safe CF3-derivatived anion (e.g.,
CF3SO2 ) by an inorganic hypervalent iodine oxidant would
generate the CF3 radical, which adds to the unsaturated bonds,
followed by capture of the reducing substance iodine to form β-
CF3 iodides. It is known that the Langlois reagent, sodium
trifluoromethanesulfinate (NaSO2CF3), can be used as an
Initially, various inorganic iodines as the potential single-
electron oxidants to trigger the reaction of alkenes with
CF3SO2Na have been screened (Table 1; see also the
Supporting Information). We found that the oxidants and
solvent critically affect the efficiency of the reaction. I2O5 was
−
9
−
inexpensive and stable trifluoromethyl anion (CF3 ) source,
Received: May 15, 2014
which has been applied in oxidative free-radical trifluoro-
© XXXX American Chemical Society
A
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Letter
a
1−6). A mixed solvent of CH2Cl2/H2O was shown to be more
effective than others such as CH3CN/H2O, tBuOH/H2O,
acetone/H2O, and AcOH/H2O (Table 1, entries 7−10).
With the optimized reaction conditions in hand, iodotri-
fluoromethylation of a broad range of olefins with CF3SO2Na
and I2O5 was studied (Scheme 2). As depicted in Scheme 2,
various aryl- and alkyl-substituted alkenes give β-CF3 alkyl
iodide as the major product in moderate to high yields under
the typical reaction conditions. Diverse functional groups such
as halogens (F, Cl, Br), NO2, sulfonate, sulfamide, carboxylate,
amide, ether, carbonyl, and hydroxyl can be well-tolerated in
this system (1−40). Terminal and nonterminal alkenes are all
compatible with this novel approach, but when both of the
double bonds are in one substrate, the iodotrifluoromethylation
selectively occurs at the terminal position (38 and 39). In
addition, this reaction can be easily scaled up to gram level
(21). Interestingly, the efficiency of the scaled-up reaction
substantially increases (21, 0.2 mmol of alkene, 20 h, 90% yield;
4.0 mmol of alkene, 3 h, 83% yield), which suggests that this
method could be potentially applied in the chemical industry.
Furthermore, products β-CF3 alkyl iodides are very useful
synthons, which can be easily converted into various classes of
compounds such as amine, alcohol, azide, ether, ester, cyanide,
Table 1. Modification of the Typical Reaction Conditions
yield
b
entry
oxidant (equiv)
PhI(OAc)2 (2)
solvent
(%)
1
2
CH2Cl2/H2O (4/1, 4.5 mL)
PhI(OCOCF3)2 (2) CH2Cl2/H2O (4/1, 4.5 mL)
5
3
IBX (2)
DMP (2)
HIO3 (4)
I2O5 (2)
I2O5 (2)
I2O5 (2)
I2O5 (2)
I2O5 (2)
CH2Cl2/H2O (4/1, 4.5 mL)
CH2Cl2/H2O (4/1, 4.5 mL)
CH2Cl2/H2O (4/1, 4.5 mL)
CH2Cl2/H2O (4/1, 4.5 mL)
CH3CN/H2O (4/1, 4.5 mL)
t-BuOH/H2O (4/1, 4.5 mL)
CH3COCH3/H2O (4/1, 4.5 mL)
AcOH/H2O (4/1,4.5 mL)
4
5
53
90
10
5
6
7
8
9
10
a
Reaction conditions: alkene (1 equiv, 0.2 mmol), NaSO2CF3 (3
b
equiv, 0.6 mmol), 110 °C, 26 h, sealed tube. Isolated yields.
more efficient than organic hypervalent iodine compounds such
as PhI(OAc)2, PhI(OCOCF3)2, 2-iodoxybenzoic acid (IBX),
Dess-Martin periodinane (DMP), and HIO3 (Table 1, entries
a
Scheme 2. I2O5-Mediated Iodotrifluoromethylation of Alkenes
a
Reaction conditions: alkene (1 equiv, 0.2 mmol), NaSO2CF3 (3 equiv, 0.6 mmol), I2O5 (2 equiv, 0.4 mmol), CH2Cl2/H2O (4/1, 4.5 mL), 110 °C,
b
c
d
sealed tube. Isolated yields. 90 °C. Obtained as a mixture of diastereoisomers. The diastereomeric ratio determined by 19F NMR spectroscopy.
B
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Letter
and so on via the well-known nucleophilic substitution. In
contrast to the previously reported strategies for alkene
iodotrifluoromethylation that require gaseous CF3I,8 our
strategy holds the advantages of easy operation and using
safer and more easily handled CF3 source (NaSO2CF3).
We next turned our attention to the iodotrifluoromethylation
of alkynes by using this method. As illustrated in Scheme 3,
radicals were clearly observed by using 2-methyl-2-nitroso-
propane (MNP) as a radical spin trap. As depicted in Scheme
4a, single-electron oxidation of NaSO2CF3 by I2O5 would
generate CF3 radical, which is quickly trapped by MNP to form
the relatively stable trifluoromethyl t-butyl nitroxide radical A
(Scheme 4b, (i), g = 2.0061, aN = aF = 12.25 G).13
Subsequently, addition of the CF3 radical to alkene would
lead to β-CF3 alkyl radical B, which adds to MNP forming
radical C. It can be seen from Scheme 4b that the information
on the key radical intermediates A and C1 (g = 2.0057, aN =
14.75 G, aH = 3.58 G) in the iodotrifluoromethylation of 2-
vinylnaphthalene has been recorded by ESR studies. To further
confirm the generation of radicals B and C, iodotrifluoro-
methylation of 2-(prop-1-en-2-yl)naphthalene in the presence
of MNP has been carried out. As shown in Scheme 4b (iii),
radicals A and C2 (g = 2.0055, aN = 15.46 G) have also been
detected by ESR through spin trapping technology. As
expected, the signal of the β-CF3 alkyl nitroxide radical
changed from sextet to triplet without the β-hydrogen (C1 vs
C2). For the formation of the CF3-substituted iodide product,
the final step might involve the capture of radical B by I2, which
is formed from I2O5 via a multistep redox process. Although the
mechanistic details of this process are not very clear now, the
formation of I2 has been confirmed by observation of a color
change from red to deep blue when starch was added into the
solution. Overall, this iodotrifluoromethylation of alkenes does
involve an atom transfer process, which is supported by the
ESR studies.
In summary, we have developed a safe, scalable, and
operationally easy iodotrifluoromethylation of alkenes and
alkynes by using two simple solids, NaSO2CF3/I2O5, in
aqueous medium. This strategy allows convenient access to a
series of useful CF3-containing building blocks such as β-CF3
alkyl iodides and β-CF3 alkenyl iodides. Additionally, the key
intermediates such as CF3 and β-CF3 alkyl radicals are clearly
observed by spin trapping technology via ESR studies, which
confirms that the free-radical process is involved in this system.
This strategy is expected to be applicable to the trifluoro-
methylation of manifold biomolecules, pharmaceutical candi-
dates, and materials. Further studies on this system are
underway in our laboratory.
Scheme 3. I2O5-Mediated Iodotrifluoromethylation of
a
Alkynes
a
Reaction conditions: alkyne (1 equiv, 0.2 mmol), NaSO2CF3 (3
equiv, 0.6 mmol), I2O5 (3 equiv, 0.6 mmol), NaHCO3 (5 equiv, 1.0
mmol), and ClCH2CH2Cl (DCE)/H2O (4/1, 3.5 mL), 110 °C, 22 h,
b
c
sealed tube. Isolated yields. Ratio of the E/Z isomers determined by
19F NMR spectroscopy.
various aryl- and alkyl-substituted alkynes are amenable to this
novel protocol. A series of (E)-β-CF3 alkenyl iodides were
obtained by reaction of alkynes with CF3SO2Na/I2O5 with the
assistance of NaHCO3 (2a−2h). It is noteworthy that the CF3-
substituted vinyl iodides can serve as valuable synthetic building
blocks in versatile coupling reactions. Notably, stereospecific
reduction of the (E)-β-CF3 alkenyl iodides allows CF3-
containing (Z)-olefins to be prepared (see Supporting
Information). On the other hand, elimination reaction of β-
CF3 alkyl iodides with a base would selectively give the CF3-
substituted (E)-alkenes. The selective preparation of both cis-
and trans-isomers of CF3-bearing alkenes makes this system
very attractive.
ASSOCIATED CONTENT
■
S
* Supporting Information
In order to confirm our hypothesis for this single-electron
oxidative free-radical process, a series of mechanistic studies by
electron spin resonance (ESR) have been carried out (Scheme
4). The ESR signals of CF3 radical as well as β-CF3 alkyl
Full experimental details and characterization data for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
Scheme 4. (a) Proposed Mechanism and Spin Trapping of
the Radical Intermediates and (b) ESR Spectra of Radicals
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: liuzhq@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project is supported by the National Science Foundation
of China (No. 21272096). We also thank Professors Bo Zhou,
Xiangfeng Shao, Wei Yu, and Long-Min Wu (State Key
Laboratory of Applied Organic Chemistry, Lanzhou University,
P.R. China) for helpful discussions.
C
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