Pd-Catalyzed Stereoselective Carboperfluoroalkylation of Alkynes

Article abstract of DOI:10.1021/jacs.5b07432

A Pd-catalyzed three component reaction involving terminal alkynes, boronic acids, and perfluoroalkyl iodides is presented here. Trisubstituted perfluoroalkenes can be obtained in a highly regio- and stereocontrolled manner by the simultaneous addition of both aryl and C_nF_m groups across the triple bond in a radical-mediated process. The reaction is operationally simple offering a broad scope and functional group tolerance.

Full text of DOI:10.1021/jacs.5b07432

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Pd-Catalyzed Stereoselective Carboperfluoroalkylation of Alkynes
Zhaodong Li, Andres García-Domínguez, and Cristina Nevado
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 26 Aug 2015
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Pd-Catalyzed Stereoselective Carboperfluoroalkylation of Al-
kynes
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Zhaodong Li, Andres García-Domínguez and Cristina Nevado
Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH 8057
Supporting Information Placeholder
close a novel Pd-catalyzed three component reaction in
ABSTRACT: A Pd-catalyzed three component reaction in-
which two new C-C bonds are simultaneously formed by
addition of perfluoroalkyl halides and boronic acids to al-
kynes producing trisubstituted perfluoroalkylated alkenes in
a highly regio- and stereoselective manner (Scheme 1, c).
volving terminal alkynes, boronic acids and perfluoroalkyl
iodides is presented here. Trisubstituted perfluoroalkenes
can be obtained in a highly regio- and stereocontrolled man-
ner by the simultaneous addition of both aryl and CnFm
groups across the triple bond in a radical-mediated process.
The reaction is operationally simple offering a broad scope
and functional group tolerance.
As a result of the unique solubility, cell permeability and
metabolic stability observed for organofluorine compounds,1
the efficient introduction of fluoroalkyl motifs in commonly
used building blocks has attracted increasing attention.2 In
contrast to the recent significant progress in the fluoroalkyla-
tion of aromatic compounds,3 efficient methods to access
fluoroalkylated alkenes are less abundant. Common strate-
gies include transition metal mediated cross-coupling reac-
tions of fluoroalkyl species with alkenyl halides as well as
fluoroalkyl radical addition and elimination reactions on
alkenes (Scheme 1, a).4 More straightforward approaches
enabling additional functionalization have been explored
with alkynes as starting materials and thus the hydro-,5 oxy-,6
amino-trifluoromethylation7 as well as the iodo-
perfluoroalkylation8 of alkynes have been recently reported.9
Carbotrifluoromethylations to simultaneously construct C-C
and C(sp2)-CnFm bonds across the C≡C bond have also been
explored, but the portfolio of these reactions is still limited to
intramolecular settings.10,11 Alternatively, multistep-processes
involving first an alkyne iodoperfluoroalkylation followed by
classical Pd-catalyzed cross couplings have also been de-
scribed to produce trisubstituted perfluoroalkenes (Scheme 1,
b).8a-c Most of the above-mentioned processes either require
the preparation of alkenyl halides and/or fluoroalkyl radical
precursors, which can be time-consuming and tedious, or
rely on the use of electrophilic CF3 sources such as Togni or
Umemoto reagents,12 which are expensive or require multi-
step synthesis. Furthermore, functionalization of alkynes via
transition metal catalysed multicomponent reactions has
been studied extensively although, with few exceptions,13
multi-step protocols using sensitive, highly reactive metal
species are required and thus competitive homo- and/or
cross-coupling reactions are present in these transfor-
mations.14 Thus, driven by our interest in radical reactions
and fluorine chemistry,15 we decided to explore the possibil-
ity of a one-pot intermolecular carboperfluoroalkylation
reaction with alkynes as starting materials. Herein, we dis-
Scheme 1. Comparison of methods to produce perflu-
roalkyl alkenes
The addition of n-perfluorobutyl iodide and 4-biphenyl-
boronic acid to phenyl acetylene was selected as benchmark
reaction (Table 1).16 In the presence of
4 mol% of
PdCl2(PPh3)2 and 2 equiv. of K2CO3 in THF, CH3CN, 1,4-
dioxane or acetone, only traces of the desired product were
formed (Table 1, entry 1). Using dichloromethane as solvent,
in the absence as well as in the presence of water, 1a was
obtained in moderate yields (Table 1, entries 2-3). Increasing
the amount of the n-perfluorobutyl iodide resulted in an
optimized 81% isolated yield for 1a, which was obtained as a
single regio- and stereoisomer (Table 1, entry 4). The re-
placement of water by other protic solvents as well as the
change of base to Cs2CO3 or catalyst to Pd(PPh3)4 did not
increase the yield of product 1a either (Table 1, entries 5-8).
With the optimized reaction conditions in hand (Table 1,
entry 4), we set out to explore the scope of this transfor-
mation.
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corporated across a set of unactivated olefins providing the
1
2
3
corresponding trisubstituted alkenes in excellent yields and
good levels of sterecontrol in favour of the thermodynamical-
ly favoured E-olefin (2l-s).
Table 1. Optimization of the reaction conditions
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Table 2. Reaction scope on boronic acid and alkynesa
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Entrya
Catalyst
Solvent
Base
Yield
of 1a
(%)d
8
(4 mol%)
(2 equiv)
9
1a
PdCl2(PPh3)2
THF, CH3CN,
1,4-dioxane,
Me2CO
K2CO3
trace
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2a
3a
PdCl2(PPh3)2
PdCl2(PPh3)2
DCM
K2CO3
K2CO3
57
62
DCM/H2O
4b
5b
6b
7b,c
8b
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
Pd(PPh3)4
DCM/H2O
DCM/EtOH
DCM/H2O
DCM/H2O
DCM/H2O
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
85(81)
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aConditions: phenyl acetylene (1 equiv), boronic acid (1.3
equiv), n-perfluorobutyl iodide (2 equiv), 0.2 M. Solvent:H2O
(5:1) if applied. b n-Perfluorobutyl iodide (3 equiv). c 1 equiv of
d
base.
Yield determined by 1H NMR with p-
nitroacetophenone as internal standard. In brackets: isolated
yield after column chromatography.
a Optimized conditions, Table 1, entry 4. b Isolated yield after
First, different aryl boronic acids were investigated in combi-
nation with phenyl acetylene (Table 2, top). Oxygen-based
electron-donating groups in the aromatic ring were well
tolerated and produced the corresponding difunctionalized
products in excellent yields and complete regio- and stere-
oselectivity (1a-d). The presence of alkyl groups had also a
positive influence in the reaction outcome, even in the case
of sterically-demanding ortho-substituted substrates, as
demonstrated by the high yields obtained for products 1e-g.
Not only phenyl boronic acid, but also the corresponding
pinacol ester and the potassium trifluoroborate proved to be
amenable substrates under these conditions (1h). Naphthyl,
cinnamyl, octenyl as well as heteroaryl boronic acid could be
coupled in moderate to high yields (1i-m). Halogen groups
(1n-p) were also well tolerated, whereas the presence of
electron-withdrawing groups seems to limit the reaction
efficiency as demonstrated in 1q-s. More elaborated boronic
acids could also be successfully involved as shown by com-
pounds 1t and 1u, respectively. In all studied cases, the prod-
ucts were obtained with perfect regio- and stereocontrol as
single isomers.
The substitution pattern on the alkyne was explored next
(Table 2, bottom). Using p-tertbutyl-phenyl boronic acid as
partner, aryl alkynes bearing both electron-donating as well
as electron-withdrawing groups were submitted to the
standard reaction conditions providing the corresponding
trisubstituted olefins in high yields and complete stereocon-
trol in favor of the E isomer (2a-k). The structure of 2h could
be confirmed by X-Ray diffraction analysis.17 The presence of
a 2-thiophene or a bulky triisopropylsilyl group seemed to
compromise the reaction efficiency (2j, 2k). Alkyl substituted
alkynes proved to be suitable partners for the present difunc-
tionalization reaction. Different boronic acids could be in-
c
column chromatography. Conditions: alkyne (1.5 equiv),
d
boronic acid (1 equiv), and then as in Table 1, entry 4. 1H
NMR yield with p-nitroacetophenone as internal standard. e
h
With PhBpin. f With PhBF3K. g 75% yield in 2 mmol scale.
10:1 E/Z ratio determined by 19F NMR. i 6:1 E/Z ratio. 4-Biphe:
4-Biphenyl-.
Different perfluoroalkyl halides were also investigated as
shown in Scheme 2. Except for trifluoromethyl and bulky
perfluoroisopropyliodide (3d and 3g), the corresponding
arylperfluoroalkylated products (3a-c, 3d-f, 3h) could be
obtained in comparable yields to those reported in Table 2.
Scheme 2. Reaction scope on perfluoroalkyl iodides
a
Conditions: alkyne (1.5 equiv), boronic acid (1 equiv), and
then as in Table 1, entry 4. b All compounds obtained as sin-
gle isomers except 3d which was isolated in a 11:1 E/Z ratio
(determined by 19F NMR). 4-Biphe: 4-Biphenyl-.
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More elaborate substrates such as estrone-derived boronic
ates in these transformations (path III). However, the reac-
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8
acid 4 and alkyne γ-tocopherol-containing alkyne 6 could be
successfully transformed into the corresponding car-
boperfluoroalkylated products 5 and 7 respectively in good
yields (equations 1 and 2).18
tions shown at the bottom of Scheme 3 disfavour this hy-
pothesis. The selectivity in favour of the E isomer also rules
out a reaction mechanism involving the direct perfluoroalkyl
palladation of the alkyne via putative Rf-Pd(II)-I intermedi-
ate (path IV), in line with the highly unreactive nature to-
wards unsaturated moieties reported for these complexes.23
As such, the high stereoselectivity can be explained based on
the less steric demand of a fast-interconverting E/Z vinyl
radical D25 for recombination with an external radical from
the opposite side to that in which the perfluoroalkyl group
has been incorporated.
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In summary,
a simple, functional-group tolerant, Pd-
catalyzed three component reaction of terminal alkynes with
boronic acids and perfluoroalkyl iodides is reported. This
method, involving the simultaneous addition of both ar-
yl/alkenyl and perfluoroalkyl group across the alkyne stream-
lines the access to perfluroalkylated trisubstituted alkenes in
a highly regio- and stereocontrolled manner in what seems
to be a radical-mediated process with broad scope and wide
synthetic applicability.
Control experiments were also designed to interrogate the
reaction mechanism. Addition of TEMPO, BHT or 1,4-
dinitrobenzene to the reaction mixture supressed, or sub-
stantially compromised, product formation.16 The reaction of
enyne 8 seems to support a radical mediated process, in
which addition of C4F9 to the more reactive alkene moiety
takes place followed by cyclization and trapping of the re-
sulting vinyl radical to give 9 (Scheme 3, top). In this reac-
tion, vinyl iodides could also be detected,16 prompting us to
carry out the reactions of 1-hexyne and phenylacetylene in
the absence of boronic acid in order to check whether iodo-
perfluoroalkylation products 10a-b could be produced under
our standard conditions. As shown in the second half of
Scheme 3, neither PdCl2(PPh3)2 nor Pd(PPh3)4 as catalysts
managed to produce significant amounts of 10, thus ques-
tioning vinyl iodides as effective intermediates in these trans-
formations.19
Scheme 4. Proposed reaction mechanism
Scheme 3. Control experiments
Although multiple scenarios can be envisaged, based on
these and additional control experiments,16 we propose the
following mechanism for these transformations. Palladium
not only is a good cross-coupling catalyst,20 but has also been
successfully used as a single electron donor.21 As depicted in
Scheme 4, the electrophilic perfluoroalkyl radical A can be
formed by reaction of Pd(0) (generated in situ with the aid of
boronic acid)21 with Rf-I.23,24 The perfluoroalkyl radical could
add intermolecularly to the C≡C affording vinyl radical D.
The subsequent recombination with either Pd(I)R2 (C) or
Pd(I)I (B) (paths I and II respectively) would finally give the
key palladium species E, which undergoes reductive elimina-
tion to produce the corresponding fluoroalkylated alkenes
while regenerating Pd(0). Alternatively, a third pathway can
be proposed involving the formation of the corresponding
iodoperfluoalkyl alkenes G as potential reaction intermedi-
ASSOCIATED CONTENT
Supporting Information
Supplementary information including compound synthesis
and characterization, crystallographic data. This material is
available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Cristina Nevado* (cristina.nevado@chem.uzh.ch)
Notes
The authors declare no competing financial interests.
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10. Gao, P.; Shen, Y.-W.; Fang, R.; Hao, X.-H.; Qiu, Z.-H.; Yang,
ACKNOWLEDGMENT
F.; Yan, X.-B.; Wang, Q.; Gong, X.-J.; Liu, X.-Y.; Liang, Y.-M.
Angew. Chem. Int. Ed. 2014, 53, 7629.
1
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3
4
5
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7
8
We thank the European Research Council (ERC Starting
grant agreement no. 307948), the Swiss National Science
Foundation (200020_146853) and the Novartis Post-Doctoral
program for financial support. We thank Prof. Dr. Anthony
Linden for the X-Ray crystal structure determination of 2h
and Dr. Estíbaliz Merino for her support in the initial stages
of the project.
11. (a) Li, Y. W.; Lu, Y.; Qiu, G.; Ding, Q. Org. Lett. 2014, 16,
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16. For additional experiments, see Supporting Information.
17. X-Ray diffraction analysis data for 2h are available from the
CCDC database: CCDC 1411445.
18. Reaction performed using 1 equiv of boronic acid and 1.5
equiv of alkyne.
19. Independently prepared perfluoroalkyl iodoalkenes 10a and
10b could be efficiently engaged in Pd-cross coupling reac-
tions with boronic acids: as already shown in ref. 8a-c. See SI.
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22. Traces of biaryls stemming from homocoupling of the bo-
ronic acids could be detected in the crude reaction mixtures.
See Ref. 16.
9
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