Iron-catalyzed 1,2-addition of perfluoroalkyl iodides to alkynes and alkenes

Article abstract of DOI:10.1002/anie.201402511

Iron catalysis has been developed for the intermolecular 1,2-addition of perfluoroalkyl iodides to alkynes and alkenes. The catalysis has a wide substrate scope and high functional-group tolerance. A variety of perfluoroalkyl iodides including CF₃I can be employed. The resulting perfluoroalkylated alkyl and alkenyl iodides can be further functionalized by cross-coupling reactions. This methodology provides a straight-forward and streamlined access to perfluoroalkylated organic molecules.

Full text of DOI:10.1002/anie.201402511

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Angewandte
Communications
DOI: 10.1002/anie.201402511
Synthetic Methods
Iron-Catalyzed 1,2-Addition of Perfluoroalkyl Iodides to Alkynes and
Alkenes**
Tao Xu, Chi Wai Cheung, and Xile Hu*
Abstract: Iron catalysis has been developed for the intermo-
lecular 1,2-addition of perfluoroalkyl iodides to alkynes and
alkenes. The catalysis has a wide substrate scope and high
functional-group tolerance. A variety of perfluoroalkyl iodides
including CF3I can be employed. The resulting perfluoroalky-
lated alkyl and alkenyl iodides can be further functionalized by
cross-coupling reactions. This methodology provides a straight-
forward and streamlined access to perfluoroalkylated organic
molecules.
T
he introduction of fluorine atoms into organic molecules
often leads to dramatic changes in their properties such as
solubility, metabolic stability, and bioavailability.[1] Addition-
ally, fluoroalkyl groups, especially the trifluoromethyl group,
are strongly electron-withdrawing and highly hydrophobic.
Because of these desirable properties, fluoroalkylated com-
pounds are widely used in materials science, argochemistry,
and medicinal chemistry.[2] Efficient and general method-
ologies for the synthesis of fluoroalkylated organic molecules,
therefore, are in high demand.[3]
Scheme 1. Comparison of various methods for the perfluoroalkylation
of alkenes and alkynes.
compounds are less costly and more suitable for large-scale
synthesis.[8] Moreover, our method allows the incorporation
of both CF3 and I functional groups into an alkyne or alkene
without generating a byproduct from the perfluoroalkylating
reagent. Therefore, it is comparatively more atom econom-
ical. Furthermore, the method can be applied to perfluor-
oalkylation which is less developed.[9]
As alkenes and alkynes are ubiquitous feedstock materi-
À
als, trifluoroalkylation of unsaturated C C bonds is an
attractive method to introduce the trifluoalkyl groups into
organic molecules.[4] Significant progress has been made
recently in copper- and silver-catalyzed allylic trifluorome-
thylation [Eq. (1), Scheme 1],[4c–f] transition-metal-catalyzed/
metal-free electrophilic oxytrifluoromethylation of alkynes
and olefins [Eq. (2)],[5] and copper-catalyzed trifluoromethy-
lazidation of alkenes [Eq. (3)].[6] The trifluoromethylating
reagents employed in these studies are often electrophilic CF3
sources such as the Togni reagent (A) and the Umemoto
reagent (B), and sometimes the nucleophilic CF3 source
TMSCF3 (Ruppertꢀs reagent; C) is used. The reagents A and
B are expensive, and C requires an activating agent such as
a fluoride and thus poses a constrain in the functional-group
compatibility.[7] Herein, we describe an iron-catalyzed 1,2-
addition of perfluoroalkyl iodides to alkynes and alkenes.
Compared with A–C, perfluoroalkyl iodides and related
Addition of perfluoroalkyl ioides to alkynes had previ-
ously been achieved using a radical initiator such as AIBN,[10a]
Et3B,[10b,c] Na2S2O3,[10d] or light.[10e] However, these reactions
had a very limited substrate scope. Only less than ten
examples of simple alkynes and several perfluoralkylating
reagents could be applied. Additionally, trifluoromethylation
was hard to achieve using these methods. The light-induced
addition of perfluoroalkyl iodides to alkenes and alkynes has
been improved in recent years. Stephenson and co-workers
reported visible-light-induced radical addition of perfluor-
oalkyl halides to alkynes and alkenes.[11a] Cho and co-workers
also reported visible-light photoredox catalysis for the
trifluoromethylation of alkynes with CF3I to give alkynyl
and alkenyl CF3 products.[11b] Nevertheless, these reactions
require precious iridium and ruthenium photocatalysts. On
the contrary, the iron-catalyzed perfluoroalkylation method
described herein requires only the inexpensive, environ-
mentally friendly, and ligandless FeBr2 as the catalyst.[12] The
reaction protocol is operationally simple, the substrate scope
is large, and the functional-group tolerance is excellent.
The addition of perfluorobutyl iodide to 1-octyne (1a)
was chosen as the test reaction (Table 1). In the presence of
Cs2CO3, FeBr2 could catalyze this reaction in high yields with
a catalyst loading of only 5 mol% (entries 1–3). Cobalt,
nickel, and copper also catalyzed the same reaction, but often
in lower yields (see Table S1 in the Supporting Information).
[*] Dr. T. Xu, Dr. C. W. Cheung, Prof. Dr. X. L. Hu
Laboratory of Inorganic Synthesis and Catalysis
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne (EPFL)
ISCI-LSCI, BCH 3305, 1015 Lausanne (Switzerland)
E-mail: xile.hu@epfl.ch
Homepage: http://lsci.epfl.ch
[**] This work is supported by a starting grant from the European
Research Council (ERC), number 257096.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402511.
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Table 1: Optimization of reaction conditions.[a]
Table 2: Scope of the iron-catalyzed addition reaction of RfI to alkynes.[a]
Entry Cat. (mol%)
RfI
(equiv)
Base (equiv)
Conv. Yield [%]
[%]
1
2
3
4
5
6
7
8
FeBr2 (10)
FeBr2 (10)
FeBr2 (5)
FeCl2 (10)
1.2
1.5
1.5
1.5
Cs2CO3 (1.5)
Cs2CO3 (1.5)
Cs2CO3 (1.5)
Cs2CO3 (1.5)
Cs2CO3 (1.5)
Et3N (1.5)
tBuOLi (1.5)
tBuOK (1.5)
pyridine
96
95
95
97
95
59
99
97
11
99
8
68
92
90
87
67
44
0
0
[Fe(acac)3] (10) 1.5
FeBr2 (5)
FeBr2 (5)
FeBr2 (5)
FeBr2 (5)
FeBr2 (5)
FeBr2 (5)
FeBr2 (5)
–
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
9
0
10[b]
11[c]
12
13
14[b]
Cs2CO3 (0.8)
Cs2CO3 (0.8)
–
95 (87)
0
0
0
0
0
–
–
Cs2CO3 (0.25) 96
95 (87)
[a] The reactions were conducted on a 0.5 mmol scale under N2. Unless
otherwise specified, yields were determined by GC for the screening
reactions using n-decane as the internal standard. [b] The yield of the
isolated product is given within the parentheses. [c] The reaction was
conducted in the air. acac=acetylacetonate.
However, only iron catalysis was further pursued. Other iron
salts also catalyzed the reaction in similar or lower yields
(entries 4 and 5). Et3N could be used as a base, but the yield
was modest (entry 6). Other bases such as tBuOLi, tBuOK,
and pyridine could not be used (entries 7–9). The optimized
reaction conditions were 5 mol% FeBr2 as the catalyst,
1.5 equivalents of perfluorobutyl iodide as the substrate, and
0.8 equivalents of Cs2CO3 as the base. Under these reaction
conditions, the yield was 95% (entry 10). The reaction needed
to be run under a nitrogen atmosphere, because when run
open to the air no product was obtained (entry 11). Without
a base, the reaction did not occur (entries 12 and 13).
Intriguingly, this particular addition reaction also occurred
with only Cs2CO3 as the base and without FeBr2 as the
catalyst. For example, the yield was 63% using 2 equivalents
of Cs2CO3. Optimization was carried out for the Cs2CO3-
mediated or Cs2CO3-catalyzed reaction (see Table S2). The
optimized reaction conditions required a high concentration
of reagents and 0.25 equivalents of Cs2CO3, thus giving a yield
of 95% (entry 14).[13] It tuned out that this iron-free, Cs2CO3-
catalyzed method only worked for a very small number of
simple alkenes and alkynes, such as 1-octyne. On the contrary,
the FeBr2-catalyzed perfluoroalkylation method could be
applied to a great number of substrates. Therefore, the scope
of the Cs2CO3-catalyzed method is presented later on, along
with the discussion on the mechanism of the iron-catalyzed
method.
[a] Reaction conditions: alkyne (0.5 mmol), RfI (1.5 equiv), FeBr2
(10 mol%), Cs2CO3 (80 mol%), 1,4-dioxane (2 mL), 608C, 18–24 h.
Yields are those of the isolated products. [b] FeBr2 (5 mol%). [c] The yield
of the Z product was determined by GC and reported as relative to the
yield of the isolated E product. [d] RfI (2.5 mmol).
ratio generally larger than 5:1. The addition to aryl alkynes is
completely stereoselective, thus yielding only E isomers (3d,
3 f). The functional-group tolerance is high. A free hydroxy
group is tolerated (3i) and in this case, the stereoselectivity is
unusually high for an alkyl alkyne substrate (E only), possibly
because of the chelating ability of the hydroxy group. Amide
(3j, 3t), ester (3l, 3o, 3u, 3v), ketone (3e, 3n, 3r), nitrile (3q),
acetal (3g), arylhalide (3h, 3m, 3o, 3s, 3v), thioether (3k,
3p), and ether (3h, 3m, 3r, 3s) groups were all compatible.
An internal alkyne could be used as a substrate as well (3w).
Considering the important function of the CF3 group,
substantial efforts were made to investigate the scope of the
iron-catalyzed addition of CF3I to alkynes. Gratifyingly, the
method has again a broad scope and high functional-group
tolerance (Table 3). The addition was efficient in the presence
of keto, ester, amide, alcohol, ether, thioether, acetal, and
aryl-halide groups and the reactions are E selective.
With the optimized reaction conditions known, the iron-
catalyzed method was first applied to the perfluoroalkylation
of various alkynes (Table 2).[14] Not only perfluoroalkyl
iodides such as C4F9I, C6F13I, but also C6F12ClI and
EtOOCCF2I can be efficiently transformed into the corre-
sponding products. The addition is E selective, with an E/Z
The iron-based method was then expanded for perfluor-
oalkylation of alkenes. To our delight, the optimized protocol
in Table 1 also worked for alkenes (Table 4).[10f,15] Both
terminal and internal olefins could be used. When an internal
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Table 3: Scope of the iron-catalyzed addition reaction of CF3I to
alkynes.[a]
[a] Reaction conditions: alkyne (0.5 mmol), CF3I (3.0 equiv), FeBr2
(10 mol%), Cs2CO3 (80 mol%), 1,4-dioxane (2 mL), 608C, 18-24 h.
Yields are those of isolated products. [b] FeBr2 (20 mol%), Cs2CO3
(150 mol%). [c] CF3I (5.0 equiv). [d] The yield of the Z product was
determined by GC and reported as relative to the yield of the isolated
E product. [e] The alkyne was treated with CF3I (3.0 equiv) twice.
Table 4: Scope of the iron-catalyzed addition reaction of RfI to alkenes.[a]
Scheme 2. Further functionalization of addition products by cross-
coupling reactions. NMP=N-methylpyrrolidone, TEA=triethylamine,
THF=tetrahydrofuran, THP=tetrahydropyranyl.
iron-catalyzed alkenyl–alkyl Kumada coupling gave 6a in
a 69% yield (Scheme 2a) and palladium-catalyzed Suzuki
coupling and Sonogashira coupling gave 6b, 6c, and 6d in
À
high yields (Scheme 2b–d). Copper-catalyzed C S bond
formation and iron-catalyzed alkyl–alkynyl Kumada coupling
furnished 6e and 6 f in good yields (Scheme 2e,f). The
neighboring perfluoroalkyl groups do not impede the cou-
pling reactions.
Several experiments were conducted to probe the involve-
ment of radicals in the iron-catalyzed reactions (Scheme 3).
When an ether-tethered enyne (1x) was used as the substrate,
ring-closed products were formed (Scheme 3a). The major
product 3x results from the the addition of C6F13 to the alkene
[a] Reaction conditions: alkene (0.5 mmol), RfI (generally 1.5 equiv; for
CF3I, 3.0 equiv), FeBr2 (10 mol%), Cs2CO3 (80 mol%), 1,4-dioxane
(2 mL), 608C, 18–24 h. Yields are those of isolated products. [b] FeBr2
(5 mol%). [c] CF3I (5.0 equiv), FeBr2 (20 mol%), Cs2CO3 (150 mol%).
[d] 808C.
olefin was used, the diastereoisomers were obtained in a 1:1
ratio (5h). Again ester, keto, aryl-halide, and ether groups
were tolerated. An estrone derivative could be smoothly
perfluoroalkylated (5i), thus demonstrating the utility of the
method for the functionalization of natural products.
The iron-catalyzed addition of perfluoroalkyl iodides to
alkenes and alkynes produces perfluoalkylated molecules
with a neighboring alkyl or vinyl iodide functional group. The
I group is a versatile leaving group for further functionaliza-
tion, for example, by cross-coupling reactions. This versatility
was demonstrated in a series of examples in Scheme 2.[16] An
Scheme 3. Reactions to probe the involvement of radicals in the
catalysis.
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and I to the alkyne, while the minor product 3x’ results from
the addition of C6F13 to the alkyne and I to the alkene.[17]
When the cyclopropyl-containing alkyne 1y was used as the
substrate, both the cyclopropyl-containing product 3y and
allene-containing product 3y’ were produced in about 40%
yield each (Scheme 3b). The outcomes of the reactions are
consistent with the formation of a perfluoroalkyl radical and
its addition to alkene or alkyne to form an alkyl or alkenyl
radical, which is prone to ring-closing cyclization or ring-
opening rearrangement. The involvement of a radical was
further collaborated by the quenching of the perfluoroalky-
lation reaction in the presence of TEMPO (1.0 equiv).
Figure 1. A tentative catalytic cycle for the catalysis.
As mentioned above, for certain simple alkynes and
alkenes, Cs2CO3 can catalyze the addition of perfluoroalkyl
iodides without the iron catalyst. Table 5 shows the scope of
with an iodide radical generated from Step 1 (step 3, Path A).
Alternatively, the carbon radical can react with another
molecule of perfluoroalkyl iodide to give the addition product
and regenerate the perfluroalkyl radical (step 3, Path B).
While the role of iron in activating alkenes and alkynes is
confirmed by the drastically different scopes of the iron-
catalyzed and iron-free reactions, the iron catalyst might
additionally act in concert with Cs2CO3 to activate the
perfluoroalkyl idodides.
Table 5: The substrate scope of the Cs2CO3-catalyzed addition reaction.[a]
In summary, a simple, broadscope, and tolerant iron-
catalyzed perfluoroalkylation method is reported. This meth-
odology provides a streamlined access to perfluoroalkylated
organic compounds starting from readily available alkenes
and alkynes. The synthetic utility of the addition products is
demonstrated in a series of transition-metal-catalyzed cross-
coupling reactions.
Received: February 17, 2014
Published online: March 28, 2014
[a] Reaction conditions: alkyne or alkene (1.0 mmol), RfI (1.5 equiv),
Cs2CO3 (25 mol%), dioxane (2 mL), 608C, 18–24 h. Unless otherwise
specified, yields are those of isolated products. [b] Yield determined by
GC.
Keywords: alkyne · cross-coupling · fluorine · iron ·
.
synthetic methods
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alkyne or alkene is functionalized, then the yield was very low
(3e, 5g). Even with simple alkyl alkenes and alkynes, the
addition of CF3I and EtOOCCF2I was inefficient (3c, 4a, 5d).
Aryl alkynes were not suitable substrates (3d, 3 f).
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Angew. Chem. Int. Ed. 2014, 53, 4910 –4914