Copper-Catalyzed Oxidative Cross-Coupling of Electron-Deficient Polyfluorophenylboronate Esters with Terminal Alkynes

Article abstract of DOI:10.1002/chem.202002888

We report herein a mild procedure for the copper-catalyzed oxidative cross-coupling of electron-deficient polyfluorophenylboronate esters with terminal alkynes. This method displays good functional group tolerance and broad substrate scope, generating cro

Full text of DOI:10.1002/chem.202002888

Accepted Article
Accepted Article
Title: Copper-Catalyzed Oxidative Cross-Coupling of Electron-Deficient
Polyfluorophenylboronate Esters with Terminal Alkynes
Authors: Zhiqiang Liu, Yudha P. Budiman, Yaming Tian, Alexandra
Friedrich, Mingming Huang, Stephen A. Westcott, Udo
Radius, and Todd B. Marder
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To be cited as: Chem. Eur. J. 10.1002/chem.202002888
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01/2020

10.1002/chem.202002888
Chemistry - A European Journal
Copper-Catalyzed
Oxidative
Cross-Coupling
of
Electron-Deficient Polyfluorophenylboronate Esters with
Terminal Alkynes
Zhiqiang Liu,[a,‡] Yudha P. Budiman,[a,c,‡] Yaming Tian,[a] Dr. Alexandra Friedrich,[a]
Mingming Huang,[a] Prof. Dr. Stephen A. Westcott,[b] Prof. Dr. Udo Radius,*[a] and Prof. Dr.
Todd B. Marder*[a]
[a] Institute of Inorganic Chemistry and Institute for Sustainable Chemistry & Catalysis with
Boron, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg (Germany)
[b] Department of Chemistry and Biochemistry, Mount Allison University, Sackville, NB E4L
1G8 (Canada)
[c]
Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas
Padjadjaran, 45363 Jatinangor, Indonesia
Abstract: We report herein a mild procedure for the copper-catalyzed oxidative
cross-coupling of electron-deficient polyfluorophenylboronate esters with terminal alkynes.
This method displays good functional group tolerance and broad substrate scope, generating
cross-coupled alkynyl(fluoro)arene products in moderate to excellent yields. Thus, it
represents a simple and alternative to the conventional Sonogashira reaction.
1
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Introduction
Functionalized aryl and heteroaryl alkynes are powerful building blocks in chemical
synthesis because of their versatility to be transformed into various useful molecules and also
their ubiquity in natural product synthesis, pharmaceuticals, and advanced materials.[1]
Consequently, much effort has been expended to develop efficient methods to install various
alkynyl groups. Some of the strategies which have been established include: (1) Sonogashira
palladium/copper-catalyzed sp2-sp cross-coupling of aryl halides with terminal alkynes;[2] (2)
direct alkynylation of unreactive alkyl and aryl C-H bonds with prefunctionalized alkynating
reagents such as alkynyl halides[3] and hypervalent iodine reagents;[4] (3) alkynylation of tetra-
and penta-fluoroarenes and heteroarenes via C-H bond activation;[5,6] and (4) cross-coupling
of copper(I) acetylides with aryl halides, known as the Castro–Stephens reaction.[7,8,9]
However, some drawbacks remain, such as the use of precious metal catalysts including those
of Pd,[2] Rh,[4a,b,h] and Au,[4c,d] strategies that depend on the use of alkynyl halides or
hypervalent iodine reagents, which are less readily available than the corresponding terminal
alkynes, and the fact that copper(I) acetylides can be heat and shock sensitive when isolated.
It is generally acknowledged that polyfluoroarenes are important fluorinated aromatic
cores and key structural units for various organic molecules, such as pharmaceuticals,
agrochemicals and organic materials.[10] The development of efficient methods to introduce
fluorine or fluorinated building blocks into organic molecules has been the subject of intense
research. Under certain conditions, Sonogashira cross-couplings involving highly fluorinated
aryl halides can be problematic, giving low yields[11a] and side reactions, i.e.,
hydrodehalogenation accompanied by homocoupling of the terminal alkyne.[11b] The latter
problem seems to arise from the slow reductive elimination of the fluoroaryl alkyne from
Pd(II), which leads to competing reverse transmetallation processes, i.e., transfer of aryl
groups from Pd to Cu in exchange for a second alkynyl moiety being transferred from Cu to
Pd. Thus, an alternative approach would be useful. In 2010, Su and co-workers
demonstrated the direct functionalization of polyfluoroarene C-H bonds with terminal alkynes,
which has proven to be a viable method to generate the corresponding alkynylated products
(Scheme 1a),[12] but this reaction is limited to C6F5H or 4-RC6F4H substrates. Soon after, the
2
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Chemistry - A European Journal
oxidative alkynylation of azoles containing acidic C-H bonds with terminal alkynes was
reported by the groups of Miura,[13] Chang,[14] and others.[15] Recently, Su and co-workers
reported a palladium-catalyzed alkynylation of heterocyclic substrates such as thiophenes and
furans.[16] Although these achievements were promising, they were restricted by elevated
temperatures (>90 °C) and limited substrate scope. In 2003, the palladium-catalyzed oxidative
cross-coupling of terminal alkynes with arylboronic acids was first disclosed by Zou and
co-workers (Scheme 1b).[17] In the past few years, various modifications of this Pd-catalyzed
reaction have been developed.[18] However, palladium is costly and only a few
electron-withdrawing substituents on the aromatic ring of arylboronic acids were employed.
Recently, Cheng et al. disclosed a copper-catalyzed oxidative coupling of arylboronic acids
with terminal alkynes.[19] However, the reported method sufferers from some disadvantages
including high reaction temperature, long reaction time (36 h), and only moderate yields.
From a synthetic point of view, the development of an improved procedure employing an
inexpensive catalyst for widespread application has remained a highly desirable goal.
We reported the C-F borylation of fluoroarenes using a NHC (N-heterocyclic
carbene)-ligated Ni complex as a catalyst to generate fluorinated arylboronic acid pinacol
esters (ArFBpin) in good to excellent yields.[20a,b] Very recently, we reported optimized
conditions for the Suzuki-Miyaura cross-coupling of ArFBpin with aryl iodides and bromides
using a combination of CuI and phenanthroline as a catalyst precursor to generate
cross-coupled products in moderate to excellent yields.[20c] We have recently reported the
palladium-catalyzed homocoupling of fluorinated arylboronates,[20d] and the borylation of aryl
chlorides, using NHC-stabilized nickel(0) complexes[20e] or a readily prepared NHC-stabilized
Cu catalyst.[20f] Inspired by these results, we attempted to develop a Cu-catalyst system for
the oxidative cross-coupling of ArFBpin compounds with terminal alkynes.
3
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Results and Discussion
We initially investigated the cross-coupling reaction with model substrates
pentafluorophenyl-Bpin (1a) and phenylacetylene (2a), using Ag2O as the oxidant and
phenanthroline (Phen) as the ligand. During our initial experiments, no reaction occurred
when CuBr2 was employed as the metal source, with tBuOLi as the base in DMF solution
(Table 1, entry 1). However, employing CuCl as catalyst precursor gave rise to compound 3a
in 10% yield (Table 1, entry 2). The introduction of Cu(OAc)2 as the catalyst precursor
improved the yield to 18% (Table 1, entry 3). However, large amounts of diyne byproduct 4
and perfluorobiphenyl compound 5 were produced.
We speculated that strong bases, such as tBuOLi, might accelerate the formation of 5.
Under otherwise identical conditions, replacing the strong base with K3PO4 effectively
4
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inhibited the homocoupling of pentafluorophenylBpin (Table 1, entry 4). To our surprise, the
addition of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) significantly improved the yield to
58% and suppressed the formation of 4 (Table 1, entry 5). It is possible that DDQ serves as an
electron-transfer mediator.[12,21] To optimize the reaction performance, we screened the
reaction parameters, including the base and the solvent. Of the bases examined, K2CO3
proved to be the most effective (entry 7). Both KF and Cs2CO3 gave significantly lower yields
(entries 6 and 8). In addition, reaction optimization also revealed that the solvent had a
significant impact on this reaction. Lower yields were observed when reactions were
performed in other solvents such as 1,2-dichloroethane (DCE), CH3CN, THF, DMSO, MTBE,
and toluene (entries 9-14). Notably, the replacement of Ag2O with O2 failed to give any
desired product (entry17), indicating the unique roles of Ag2O in promoting this reaction.
Attempts to run the reaction in air resulted in a very low yield of the desired product (entry
15). Reducing the amount of K2CO3 and Ag2O also diminished the yield (Table 1, entries 18
and 19).
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Table 1. Optimization of Reaction Conditions[a]
[Cu]
Base
Additive
Yield(%)[b]
Entry
Solvent
(15 mol%)
CuBr2
(2 equiv) (40 mol%)
3a
0
4
5
1
2
tBuOLi
tBuOLi
tBuOLi
K3PO4
K3PO4
Cs2CO3
K2CO3
KF
-
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MTBE
DCE
65
55
60
52
5
36
35
35
8
CuCl
-
10
18
35
58
11
82
15
0
3
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
-
4
-
5
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
8
6
25
3
25
4
7
8
10
5
45
35
0
9
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
10
11
12
13
14
15[c],
16[d]
17[e,f]
18[g]
19[h]
0
5
toluene
DMSO
CH3CN
THF
0
10
15
15
10
5
10
20
10
15
40
35
10
30
30
25
10
5
DMF
DMF
DMF
DMF
DMF
5
5
10
6
0
35
25
5
28
[a] Reaction conditions: 1a (0.4 mmol), 2a (0.45 mmol), Cu(OAc)2 (15 mol%),
phenanthroline (Phen, 15 mol%), Ag2O (1.8 equiv), DDQ (40 mol%), base (2.0 equiv),
anhydrous and degassed solvent (5 mL). The mixture was stirred at 40 °C under argon, in a
sealed tube for 12 h. [b] 3a: isolated yield, 4: isolated yield, 5: the yields were determined by
GC-MS analysis vs. a calibrated internal standard (n-dodecane) and are averages of two runs;
[c] The reaction was performed in air. [d] Room temperature. [e] In the absence of Ag2O. [f]
Under O2. [g] Ag2O (1.2 equiv.). [h] Base (1.0 equiv.).
With the optimized conditions in hand, we focused our attention on investigating the
scope and limitations of the oxidative cross-coupling reaction. As shown in Scheme 2, various
fluorophenylboronate esters 1 containing 1-4 fluorine atoms were tested. Under the standard
conditions (Table 1, entry 7), different tetrafluorophenylboronate esters and
trifluorophenylboronate esters smoothly underwent alkynylation giving good to excellent
6
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Chemistry - A European Journal
yields (Scheme 2, 3b-3f). However, these reaction conditions were not suitable for ArFBpin
substrates containing di- or mono-fluorinated arylboronates such as 2,5- or
2,3-difluorophenyl-Bpin (1g and 1i) and 3-fluorophenyl-Bpin (1h), perhaps due to the lower
Lewis acidity of the boronates which is impacted by the number fluorine and, especially,
ortho-fluorine substituents. We speculated that increasing the temperature might be crucial for
overcoming the barrier to C-B bond activation and thus to obtaining efficient catalysis. When
reactions were performed at 80 °C, the corresponding products 3g and 3i were formed in good
yields. It also noteworthy that replacement of the weak base with a stronger base afforded the
corresponding product in good yield (3h).
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Scheme 2. Scope of the Reaction with Respect to the Different Polyfluorophenyl
Boronate Substrates 1 [a,b]
[a] Reaction conditions: 1 (0.4 mmol), 2a (0.45 mmol), Cu(OAc)2 (15 mol %), Phen (15 mol %),
Ag2O (1.2 equiv.), DDQ (40 mol %), K2CO3 (2.0 equiv.), DMF (4 mL), 40 °C, 12 h, Ar. [b] 3:
isolated yield. [c] Ag2O (1.8 equiv.). [d] 80 oC. [e] tBuOLi.
8
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Scheme 3. Scope of the Reaction with Respect to the Different Terminal Alkyne
Substrates 2[a,b]
[a] Reaction conditions: 1a (0.4 mmol), 2 (0.45 mmol), Cu(OAc)2 (15 mol %), Phen (15 mol %),
Ag2O (1.8 equiv), DDQ (40 mol %), K2CO3 (2.0 equiv.), DMF (4 mL), 40 °C, 12 h, Ar. [b] 6:
isolated yield. [c] 24 h.
9
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The substituents of alkynes 2 were then varied, in order to explore further the scope of
the reaction. As shown in Scheme 3, a series of alkynes 2 with different electron-withdrawing
and electron-donating substituents on the aromatic ring were subjected to the optimal
conditions. The experimental results showed that a broad range of substituents on the
arylalkynes 2, including methyl, methoxy, chloro, bromo, and fluoro groups at the ortho-,
meta-, and para-positions of the aromatic ring were well tolerated, providing the desired
compounds in moderate to excellent yields (Scheme 3, 6a-6h). Furthermore, the structures of
compounds 6a and 6g were unambiguously confirmed via single crystal X-ray diffraction
(vide infra). An ester group, which may not be tolerated in reactions employing organozinc
reagents, is also compatible with this reaction (6i). Importantly, aliphatic alkynes proceeded to
give the desired products in moderate to good yields (6j and 6k). With a highly
electron-withdrawing CF3-substituent, only moderate yields were observed (6l and 6m).
Unfortunately, less reactive 4-nitro-phenyl and 4-cyano-phenyl alkynes were not suitable for
the reaction under the standard conditions.
To examine the feasibility of scaling up the reaction, a gram-scale coupling of
C6F5-Bpin with phenylacetylene was employed (Scheme 4). The desired coupling product
was obtained with minimal loss of yield (72%).
Scheme 4: Gram-Scale Synthesis of 3a
Based on previous reports,[22] and the aforementioned observations, a plausible catalytic
cycle for our oxidative cross-coupling reaction is shown in Scheme 5. The first step would
involve the addition of alkynyl anion leading to the formation of alkynylcopper(II) species B.
Subsequent transmetalation between ArFBpin and intermediate B occurs to form intermediate
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C. The desired product 3a would be generated by C-C reductive elimination. The Cu(0)
[12,21]
species formed is reoxidized by DDQ, vide supra,
to regenerate A, completing the
catalytic cycle.
Scheme 5: Proposed Mechanism
Molecular and Crystal Structures: Intermolecular ππ Stacking Interactions
The crystal structures of the cross-coupling products 6a and 6g were analyzed using
single-crystal X-ray diffraction. The molecular geometries of these compounds in their crystal
structures are shown in Figure 1. The central CC bond lengths are 1.195(2) and 1.1996(6) Å
(Table 2) and, hence, typical of CC triple bonds (1.192 Å).[23] The sp-sp2 C−C single bonds
between the alkyne and the fully fluorinated phenyl rings are slightly shorter (1.4265(7) and
1.427(2) Å) than the corresponding bonds to the mesityl ring of 6a (1.4350(7) Å) or the para
mono-fluorinated phenyl ring of 6g (1.437(2) Å). The sp-sp2 C−C bonds to tetra- or
penta-fluorinated phenyl rings are also shorter than those to the fully or mostly
hydrogen-containing phenyl rings of mixed compounds in other partially fluorinated tolans,[24]
rod-like 1,4-bis(phenylethynyl)benzenes,[25] and phenyl and perfluorophenyl end-capped
polyynes.[26] The shortening is due to the strong electron-withdrawing nature of the fluorine
atoms, and the length difference is also observed in the co-crystals of fully
hydrogen-containing
and
fully
fluorinated
tolans,[24]
rod-like
1,4-bis(phenylethynyl)benzenes,[27] and phenyl end-capped polyynes.[26] The molecules of 6a
11
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and 6g are nearly planar with a very small twist between the aryl moieties (2.959(3) and
3.04(5)°, Table 2). A small twist angle of between 0 and 6° is also typical of the hydrogenated
and fluorinated tolans, rod-like 1,4-bis(phenylethynyl)benzenes, and phenyl endcapped
polyynes.[24-27] Larger twist angles were reported for compounds related to 6g in which the
fluorine atom at the para-position of the phenyl ring is substituted by iodine (9.4(2)°),
bromine (15.69(8)°), and NO2 (9.90(7)°).[28] This may be related to the prevalence of different
intermolecular interactions in these compounds (see below).
Figure 1. Solid-state molecular structures of 6a and 6g determined by single-crystal X-ray
diffraction at 100 K. Ellipsoids are drawn at the 50% probability level, and H atoms are
omitted for clarity. Colors: white (carbon), green (fluorine).
Table 2. Selected bond lengths (Å) and angles (°) of 6a and 6g, and ππ stacking distances
(Å).
6a
6g
1.1996(6)
1.195(2)
CC triple bond
CAryl(H/F)–Ctriple
1.4350(7)
1.4265(7)
2.959(3)
1.437(2)
1.427(2)
3.04(5)
CAryl(F)–Ctriple
 Aryl(F)-Aryl(H/F)
3.586(3)
3.705(3)
centroid-centroid distance
interplanar separation
offset shift[a]
3.629(3)
3.913(3)
3.361(3) / 3.424(3)
3.325(3) / 3.376(3)
1.248(3) / 1.064(2)
1.455(2) / 1.332(2)
3.349(2) / 3.415(2)
3.379(2) / 3.438(2)
1.586(3) / 1.439(3)
1.975(3) / 1.868(3)
[a] The offset shift, also called inter-centroid shift, is the distance within a plane of an aryl
ring between the centroid of the respective aryl ring and the intersection point with the normal
to the plane through the centroid of the other aryl ring.
12
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In compounds 6a and 6g, the nearly planar molecules are related by inversion
symmetry and are oriented offset face-to-face in a head-to-tail fashion forming infinite
-stacks (Figure 2). The interplanar separations between the aromatic rings (3.325(3) –
3.438(2) Å, Table 2) are in the normal range of - stacking interactions, which are typical of
molecules for which the packing is dominated by arene-perfluoroarene interactions. The
differences in electronegativity of hydrogen and fluorine atoms with respect to the carbon
atoms leads to the formation of opposite multipoles for fully fluorinated and nonfluorinated
aryl groups and, hence, to attractive multipole forces between these groups.[29] Head-to-tail
stacking via arene-perfluoroarene interactions, analogously to that observed in 6a and 6g, is
commonly found in self-complementary compounds that contain both fluorinated and
nonfluorinated aryl groups. Examples are partially fluorinated tolans[24] and
phenyl-endcapped polyynes,[26] but also co-crystals of bis(phenylethynyl)benzenes with
inversely alternating fluorinated and nonfluorinated phenyl rings.[25] We conclude that
methylation at the 2-, 4-, and 6-positions of the phenyl ring in 6a does not alter this common
stacking motif and, hence, the influence of arene-perfluoroarene interaction on the molecular
packing. Arene-perfluoroarene -stacking was also observed in the 1:1 co-crystal of
mesitylene and hexafluorobenzene.[30] Weak intermolecular C–HF, CF, and FF
interactions exist between adjacent stacks in 6a and 6g (Figure 2, Table S2 in the Supporting
Information). Mono-fluorination at the para-position of the phenyl ring in 6g does not have a
significant influence on the arene-perfluoroarene packing, which is very similar to that of
1-pentafluorophenyl-2-phenylacetylene.[24] This was expected as the mono-chlorination of
partially fluorinated tolan at the same para position did not alter the packing motif.[28a] The
effect of halogenation with chlorine, bromine, and iodine atoms at the para-positions of
partially fluorinated tolans on the presence of arene-perfluoroarene interaction, studied earlier
by Marder and co-workers,[28a] revealed the absence of arene-perfluoroarene stacking only for
the compounds substituted with the heavier halogens (Br, I). This was explained by the
prevalence of Br···Br and I···I interactions determining the packing of the molecules.[28a] Also
note the larger twist angle between the phenyl rings in these compounds (15.69(8) and
9.4(2)°) when compared to those in arene-perfluoroarene -stacked tolans (see discussion
above). Similarly, the substitution of other strong electron-withdrawing groups such as NO2
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and CN at the para-position of the phenyl ring in partially fluorinated tolans showed the
prevalence of O···O and C–H···N interactions and the absence of arene-perfluoroarene
interactions in their crystal structures.[28b]
Figure 2. Crystal structures of (left) 6a and (right) 6g projected along (top) the stacking
direction of the molecules, and (bottom) the b and a axis, respectively, at 100 K. Molecules
are -stacked along the a axis (6a) and the b axis (6g), respectively, in alternating
orientations. Four unit cells are shown in each projection. All ellipsoids are drawn at the 50%
probability level, and H atoms are omitted for clarity. Colors: white (carbon), green (fluorine).
Red dotted lines represent intermolecular contacts which are shorter than the sum of the Van
der Waals radii.
In conclusion, we have developed a copper-catalyzed method for the direct
alkynylation of electron-deficient polyfluorophenylboronate esters with terminal alkynes.
This reaction features broad functional group tolerance, mild reaction conditions, and simple
operation. From a synthetic point of view, the present reaction has the potential to be applied
widely in organic synthesis because many shelf-stable aryl and alkyl boronate esters are
commercially available. The partially fluorinated tolans also display interesting
14
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fluoroarene-arene -stacking interactions in the solid-state as demonstrated by single-crystal
X-ray diffraction in two cases.
Crystallographic details
Crystal data collection and processing parameters are given in the Supporting Information.
CCDC-2000968 (6a), 2000970 (6g) contain the supplementary crystallographic data for this
paper. These data are provided free of charge by The Cambridge Crystallographic Data
Centre.
Author Contributions
‡
Z.L. and Y.P.B contributed equally.
ORCID
Yudha P. Budiman: 0000-0002-3929-1891
Yaming Tian: 0000-0001-5083-137X
Alexandra Friedrich: 0000-0002-1411-7336
Stephen A. Westcott: 0000-0002-5324-2295
Udo Radius: 0000-0002-0759-1806
Todd B. Marder: 0000-0002-9990-0169
Acknowledgments
Z.L. is grateful to the China Scholarship Council for providing a PhD scholarship. Y.P.B.
thanks the Indonesia Endowment Fund for Education (LPDP) for a PhD scholarship. T.B.M.
and U.R. thank the Julius-Maximilians-Universität Würzburg and the Deutsche
Forschungsgemeinschaft (DFG) for support. S.A.W. acknowledges support from the Natural
Science and Engineering Research Council of Canada. We thank AllyChem Co. Ltd. for a
generous gift of B2pin2.
Conflict of interest
The authors declare no conflict of interest.
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Keywords: boronate ester · coupling reaction · fluorine · fluoroarene · Sonogashira
reaction
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Graphical Abstract
BFF: Boron Helps Make Fluorinated Alkynes: We report a mild procedure for the
synthesis of alkynyl(fluoro)arenes via copper-catalyzed oxidative cross-coupling of
polyfluorophenylboronate esters with terminal alkynes.
21
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