[Cu(NHC)]-Catalyzed C-H Allylation and Alkenylation of both Electron-Deficient and Electron-Rich (Hetero)arenes with Allyl Halides

Article abstract of DOI:10.1002/anie.201510180

New reactivity of a [Cu(NHC)] (NHC=N-heterocyclic carbene) catalyst is disclosed for the efficient C-H allylation of polyfluoroarenes using allyl halides in benzene at room temperature. The same catalyst system also promotes an isomerization-induced alkenylation of initially the generated allyl arenes when the reaction is run in tetrahydrofuran. Significantly, not only electron-deficient but also electron-rich (hetero)arenes undergo this double-bond migration process, thus leading to alkenylated products. The present system features mild reaction conditions, broad scope with respect to the arene substrates and allyl halide reactants, good functional-group tolerance, and high stereoselectivity.

Full text of DOI:10.1002/anie.201510180

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International Edition: DOI: 10.1002/anie.201510180
German Edition: DOI: 10.1002/ange.201510180
Allylic Compounds Very Important Paper
À
[Cu(NHC)]-Catalyzed C H Allylation and Alkenylation of both
Electron-Deficient and Electron-Rich (Hetero)arenes with Allyl
Halides
Weilong Xie and Sukbok Chang*
Abstract: New reactivity of a [Cu(NHC)] (NHC = N-hetero-
À
cyclic carbene) catalyst is disclosed for the efficient C H
allylation of polyfluoroarenes using allyl halides in benzene at
room temperature. The same catalyst system also promotes an
isomerization-induced alkenylation of initially the generated
allyl arenes when the reaction is run in tetrahydrofuran.
Significantly, not only electron-deficient but also electron-rich
(hetero)arenes undergo this double-bond migration process,
thus leading to alkenylated products. The present system
features mild reaction conditions, broad scope with respect to
the arene substrates and allyl halide reactants, good functional-
group tolerance, and high stereoselectivity.
T
he introduction of an allyl or vinyl group into organic
molecules is an important step for further transformations in
organic synthesis,[1] polymer, and materials chemistry.[2] As
a result, the development of selective catalytic systems is
highly desirable for the facile construction of the unsaturated
synthons. Transition metal catalyzed allylation of aryl electro-
philes represents a powerful tool for accessing allyl arenes.[3]
À
Scheme 1. Direct C H allylation of polyfluoroarenes and isomerization-
induced alkenylation of heteroarenes.
fluoroarenes is highly valuable. In this regard, presented
herein is a new protocol for the C H allylation of fluoro-
À
À
In this context, direct C H allylation of electron-deficient
arenes by using a [Cu(NHC)] (NHC = N-heterocyclic car-
bene) catalyst under mild reaction conditions (Scheme 1b).
Interestingly, an isomerization pathway of the initially formed
allyl arenes was subsequently discovered to work efficiently
to deliver vinylarene compounds. Moreover, this catalytic
system was also successfully applied to the isomerization-
induced alkenylation of electron-rich heterocycles such as
(benzo)thiophenes and (benzo)furans. To the best of our
knowledge, this study represents the first example of direct
C H allylation and alkenylation operating with both elec-
tron-deficient and electron-rich (hetero)arenes.
Recently, copper complexes bearing NHCs have been
fruitfully utilized in various catalytic reactions.[8] In 2010,
Nolan et al. reported the use of [(IPr)Cu(OH)] [IPr= N,N’-
bis(2,6-diisopropylphenyl)-imidazol-2-ylidene] in the activa-
arenes is noteworthy since conventional approaches, such as
Friedel–Crafts allylation or arylmetal coupling reactions, are
not effectively applicable for these substrates.[3,4] Thus far,
only limited examples have been revealed for the direct
allylation of electron-deficient arenes (Scheme 1a).[5] For
instance, Miura et al. employed allyl phosphates as the allyl
source under the [Cu(acac)2]/Phen catalyst system.[5a] Zhang
et al. reported a palladium-catalyzed allylation of polyfluoro-
benzenes with either allylcarbonates or allylchlorides under
rather harsh reaction conditions.[5b,c] Meanwhile, an isomer-
ization-induced alkenylation can be envisaged to be an
attractive approach for the transformation of a pre-existing
allyl moiety into vinyl groups while leaving the other parts
intact.[6]
À
À
Considering the fact that polyfluoroarenes represent an
important structural motif in materials and medicinal chemis-
try owing to the unique property of fluorine atom,[7] the
development of efficient and selective functionalization of
tion of C H bonds of 1,2,4,5-tetrafluorobenzene in a stoichio-
metric manner.[9] In line with this work, and given our
continuing efforts on NHC chemistry,[10] it was envisaged that
[Cu(NHC)] complexes might be potent for the catalytic
allylation of polyfluorobenzenes.[11]
We commenced our study by optimizing the allylation of
pentafluorobenzene with trans-cinnamyl bromide by examin-
ing various copper catalyst systems (Scheme 2; see Table S1 in
the Supporting Information for details). It was observed that
the use of [(IiPr)CuCl] (3;[12] IiPr= 1,3-diisopropylimidazol-2-
ylidene; 2.0 mol %) in the presence of NaOtBu (1.5 equiv)
afforded an allylated product with excellent yield (5 min at
258C) when using benzene as the solvent. However, the
copper species 1, bearing IPr, was totally ineffective and the
[*] Dr. W. Xie, Prof. Dr. S. Chang
Center for Catalytic Hydrocarbon Functionalizations
Institute for Basic Science (IBS), Daejeon 305-701 (Korea)
and
Department of Chemistry, Korea Advanced Institute of Science and
Technology (KAIST), Daejeon 305-701 (Korea)
E-mail: sbchang@kaist.ac.kr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201510180.
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initially formed allyl arenes when the benzene solvent was
replaced by tetrahydrofuran (THF). A model reaction of
2,3,5,6-tetrafluoroanisole with methallyl bromide was moni-
tored by 1H NMR spectroscopy (see Figure S2). It was shown
that an alkenylated product was formed gradually over
10 hours in [D8]THF at 608C, a product arising from the
isomerization of the allylarene. Other solvents such as 1,4-
dioxane, tert-butanol, and 2,5-(Me)2-THF displayed only
moderate efficiency. A tert-butoxide base with either a potas-
sium or lithium counter cation did not result in olefin
isomerization although the exact reason is not clear at
present.
The above isomerization-induced vinylation approach
was successfully applied to a wide range of polyfluoroarene
substrates in reactions with allyl bromides in good yields
(Table 2). It is worth mentioning that the newly isomerized
double bonds were exclusively in the E conformation. The
À
Scheme 2. Catalyst screening for the C H allylation of pentafluoroben-
zene.
activity of [(IMes)CuCl] (2; IMes = N,N’-bis(2,4,6-trimethyl-
phenyl)imidazol-2-ylidene) was only moderate.
With the optimized reaction conditions in hand, a range of
allyl halides were examined in reactions with pentafluoro-
benzene (see Table S2). It was found that allyl bromide and its
alkyl-substituted derivatives reacted smoothly to afford the
corresponding allyl(pentafluoro)benzenes in high yields. Sig-
nificantly, secondary allyl bromides were also facile reactants
under the present system and a similar range of allylation
efficiency was observed even with allyl chlorides, albeit under
slightly more demanding reaction conditions (5.0 mol% of 3;
20 h; 258C).
Table 2: Scope with respect to the fluoroarenes in the isomerization-
induced alkenylation.[a]
We next examined the scope with respect to the poly-
fluoroarenes,[13] in reaction with cinnamyl bromide as a rep-
resentative reactant (Table 1). Various types of polyfluoro-
arenes were allylated in good yields without difficulty (2a–j),
and more challenging substrates such as trifluoro- or difluoro-
benzenes also reacted under the present allylation protocol.
À
Interestingly, when two equivalent C H bonds are present,
mono- and di-allylation could be controlled by changing the
stoichiometry of the allylating reagent and base (2c–f).
During the course of the allylation study, we observed an
intriguing phenomenon of double-bond isomerization of the
Table 1: Scope of polyfluoroarenes in allylation with cinnamyl bromide.[a]
[a] Reaction conditions: allyl bromides (1.0 mmol), arenes (1.05 equiv),
NaOtBu (1.5 equiv), and 3 (5.0 mol%) in THF (3.0 mL) at 608C. Yields
are those of isolated products. [b] 3 (2.0 mol %) at 258C. [c] A mixture of
allyl and alkenyl isomers (1:1). [d] Allyl bromide (3.0 equiv) and base
(3.0 equiv). [e] Allyl bromide (5.0 equiv) and base (6.0 equiv). [f] 1,2,3,4-
Tetrafluorobenzene (3.0 equiv). [g] 1,2,4,5-Tetrafluorobenzene
(8.0 equiv).
isomerization efficiency was found to be affected to some
extent by the initially introduced allyl groups. For instance,
while the double-bond migration was smooth in acyclic allyl
arenes, a cyclic olefin was isomerized less efficiently (3c).
À
Fluoroarenes bearing multiple reactive C H bonds were
alkenylated in a selective manner by controlling the stoichi-
ometry of the allyl halide. For instance, doubly vinylated
polyfluoroarenes were obtained in high yields (3d–f), and the
introduction of three 1-propenyl groups to 1,3,5-trifluoroben-
zene was also efficient (3g). In contrast, selective monoviny-
[a] Reaction conditions: Cinnamyl bromide (1.0 mmol), fluoroarene
(1.05 equiv), NaOtBu (1.5 equiv), and 3 (2.0 mol %) in C6H6 (3.0 mL) at
258C. Yields are those of the isolated products. [b] 3 (5.0 mol%). [c] Base
(2.2 equiv), cinnamyl bromide (2.2 equiv). [d] 3 (10.0 mol %). [e] Meth-
allyl bromide was used. [f] Cinnamyl chloride was used.
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À
lation among multiple reactive C H bonds was readily
performed in moderate to good yields by using allyl bromides
as the limiting reactant (3h–k).
were delighted to see that thiophenes reacted to give
alkenylated products. For instance, 2-phenylthiophene was
alkenylated in high yield (4 f). Moreover, various functional
groups such as cyano, ester, alkynyl, silyl, and amide
substituents were all compatible with the present catalytic
system (4g–k).[18] An X-ray crystallographic structure of 4k
was obtained.
It is worthwhile noting that whereas thiophene carboxyl-
ate ester was previously employed for the ruthenium-cata-
lyzed alkenylation using ester as a directing group,[17c] the
current copper catalyst system enabled C5-olefination (4h;
Table 3). Interestingly, 2,2’-bithiophene underwent the olefi-
nation twice at the 5,5’-position in quantitative yield when
using excess amounts of both methallyl chloride and
NaOCEtMe2 (4l). Similarly, alkenylation of thieno[3,2-
b]thiophene proceeded with excellent efficiency and selectiv-
ity (4m). Unsubstituted thiophene was also alkenylated
without difficulty (4n and 4n’). Furan and benzofuran
derivatives were also reacted to afford C2 alkenylated
products (4o–q). Azole heterocycles were observed to
undergo olefination in high yields (4r–t). However, the
system was not applicable for an indole derivative, presum-
ably because of its high pKa value (pKa = 37.7).[13a]
Next, we were curious about the applicability of the
present system for more challenging electron-rich hetero-
arenes. Introduction of alkenyl groups onto heteroarenes is
synthetically valuable because olefinated heteroarenes are
widely utilized in polymer and materials chemistry.[15] For this
purpose, palladium catalyst systems were previously devel-
oped, including the Fujiwara–Moritani reaction.[16] More
recently, rhodium, iridium, and ruthenium catalysts have
been examined for the introduction of vinyl groups onto
heteroarenes.[17] In this context, the development of efficient
and selective catalytic systems based on the first-row tran-
sition metals is highly desirable.
Upon the screening of reaction parameters (see Table S8),
it was found that benzothiophene reacted smoothly with
methallyl chloride in the presence of NaOCEtMe2 to give
excellent product yield (92%) at 608C in THF. As presented
in Table 3, benzothiophenes substituted with methyl or
a more labile bromo group at the 5-position underwent the
alkenylation in excellent yields (4a–c). 5-Chlorobenzo-
[b]thiophene, having a substituent at the 3-position, also
underwent the alkenylation efficiently (4d). Unsubstituted
allyl chloride could be employed without difficulty (4e). We
To shed light on the reaction pathway, a series of
mechanistic studies were designed (see the Supporting
Information for details). When [(IiPr)CuCl] (3) was treated
with a stoichiometric amount of NaOtBu and then penta-
À
À
Table 3: Scope with respect to the heteroarenes in the C H alkenyla-
fluorobenzene,
a C H activated aryl copper species,
tion.[a]
[(IiPr)Cu-C6F5] (I), was observed.[19] Although an X-ray
crystallographic analysis of I failed, its structure was con-
firmed by NMR spectroscopy. The isolated copper complex I
was readily reacted with methallyl bromide to give
[(NHC)Cu-Br] and an allylated product (1c) quantitatively,
thus strongly suggesting that I is involved in the catalytic
cycle. In addition, the observation that the stereochemistry of
the double bond of allyl bromide was transferred to the
allylated products led us to postulate that the double-bond
insertion into I most likely proceeds via a tightly bound
transition state.[5a,20]
In addition, kinetic isotope effects (KIE) were not
À
measured (kH/kD = 1.0) and imply that the C H cleavage of
polyfluoroarenes may not be connected to the turnover-
limiting stage. When the allylated arene compound 2k was
isomerized, catalytic amounts of both copper and NaOtBu
were essential to bring about the olefin isomerization, thus
leading to the vinyl arene compound 3b. For the alkenylation
of electron-rich heteroarenes, a base-promoted electron
transfer pathway can also be considered,[21] but it turned out
to be unlikely since the addition of TEMPO or 1,1-diphenyl-
ethene did not affect the reaction progress.
Based on the above results and literature prece-
dents,[5a,9,20] a proposed pathway of the present [Cu(NHC)]-
catalyzed allylation is shown in Scheme 3. A ligand exchange
of [(NHC)Cu-Cl] (A) with the base (NaOtBu) leads to
[(NHC)Cu-OtBu] (B), which is believed to react with
(hetero)arenes to form a copper-aryl intermediate (E). An
oxidative insertion of allyl halides into E is then assumed to
occur, thus giving rise to an p-allyl CuIII complex (G),
presumably through a tightly bound transition state, thus
[a] Reaction conditions: heteroarene (0.20 mmol), methallyl chloride
(1.5 equiv), base (2.0 equiv) and catalyst 3 (10.0 mol%) in THF
(0.5 mL). Yields are those of isolated products. [b] Methallyl chloride
(0.20 mmol), heteroarene (2.0 equiv), base (1.2 equiv). [c] Methallyl
chloride (5.0 equiv), base (5.0 equiv). [d] GC-MS yield. [e] NaOtBu
(1.5 equiv) used as the base.
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farnesyl bromide were readily reacted to afford the corre-
sponding products stereoselectively in high yields (Scheme 4b
and c). Despite the fact that highly conjugated thiophene
derivatives have been widely employed in synthetic and
materials chemistry,[23] preparative routes to these motifs are
mainly limited to tedious stepwise approaches. In this context,
the direct vinylation of an alkyne-substituted thiophene is
especially noteworthy (5d), in which the trimethylsilyl moiety
also reacts with the copper species presumably to form
a copper acetylene species,[24] which then undergoes allylation
followed by double-bond isomerization.
In summary, we have developed the [Cu(NHC)]-catalyzed
À
C H allylation of polyfluoroarenes by using allyl halides as
the reactants. The same catalyst system was found to also be
effective for the double-bond migration of the initially
generated allyl arenes by changing the solvent, thus leading
to vinyl arene products. This system was successfully utilized
for the alkenylation of various types of electron-rich hetero-
cycles such as (benzo)thiophenes and (benzo)furans. This
procedure features high efficiency, mild reaction conditions,
controllable selectivity, broad scope, and high functional-
group tolerance, and is thus anticipated to find utility in
synthetic, polymer, and materials chemistry.
Scheme 3. Possible mechanism for the reactions.
enabling the stereochemistry of allyl halides being transferred
to allyl arene products.[20] As the final stage, a reductive
elimination of the G affords the allylated product H with the
regeneration of catalyst [(NHC)Cu-X].
Acknowledgments
Although more comprehensive studies are required to
delineate the isomerization of the initially generated allyl
arenes to a vinyl group in THF, we assume that it is initiated
This research was supported financially by the Institute for
Basic Science (IBS-R010-D1) in Korea. We thank Jisu Jeong
(KAIST) for her helpful discussions.
À
mainly by the copper-mediated allyl C H bond activation of
allyl arenes to form a p-allyl/CuIII species, which undergoes
protonolysis by tBuOH (major pathway). This proposal is
Keywords: alkenes · allylic compounds · copper · isomerization ·
N-heterocyclic carbenes
À
based on the fact that allyl arenes bear an allyl C H bond with
pKa values lower than 34[13c] and is therefore readily depro-
tonated by [(NHC)Cu-OtBu]. However, this isomerization
was observed to take place also by NaOtBu alone, albeit with
much lower efficiency (minor pathway).
How to cite: Angew. Chem. Int. Ed. 2016, 55, 1876–1880
Angew. Chem. 2016, 128, 1908–1912
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[20] In analogy to Miuraꢀs system, a process of the s–p conversion of
the s-allyl copper species is probably much faster than the
related E/Z isomerization which will lead to erosion of the
stereochemistry. p-Allyl copper(III) intermediates are known to
give mainly SN2 products while the corresponding s-allyl
copper(III) intermediates were shown to afford SN2’ products:
a) E. R. Bartholomew, S. H. Bertz, S. Cope, M. Murphy, C. A.
Ogle, J. Am. Chem. Soc. 2008, 130, 11244; b) Rotation of s-allyl
isomers is known to be much slower than the formation of s–p
allyl copper(III) intermediates: Ref. [5a].
À
[21] For the base-promoted C H activation of arenes by an electron-
transfer pathway, see: a) C.-L. Sun, H. Li, D.-G. Yu, M. Yu, X.
Zhou, X.-Y. Lu, K. Huang, S.-F. Zheng, B.-J. Li, Z.-J. Shi, Nat.
Chem. 2010, 2, 1044; b) A. Studer, D. P. Curran, Angew. Chem.
Int. Ed. 2011, 50, 5018; Angew. Chem. 2011, 123, 5122.
[22] a) J. Llaveria, . Beltrµn, W. M. C. Sameera, A. Locati, M. M.
Díaz-Requejo, M. I. Matheu, S. Castillón, F. Maseras, P. J. PØrez,
J. Am. Chem. Soc. 2014, 136, 5342; b) Y. Zou, Z. Zhan, D. Li, M.
Tang, R. A. Cacho, K. Watanabe, Y. Tang, J. Am. Chem. Soc.
2015, 137, 4980.
[12] The structure of complex 3 was unambiguously confirmed by X-
À
ray crystallographic analysis which shows that the Cu CNHC
bond length is 1.8819(13) Š (see the Supporting Information
for details).
[13] For pKa values of polyfluoroarenes and heteroarenes, see: a) K.
Shen, Y. Fu, J.-N. Li, L. Liu, Q.-X. Guo, Tetrahedron 2007, 63,
1568; b) A. E. Wendlandt, A. M. Suess, S. S. Stahl, Angew.
Chem. Int. Ed. 2011, 50, 11062; Angew. Chem. 2011, 123, 11256;
c) K. Bowden, R. S. Cook, J. Chem. Soc. Perkin Trans. 2 1972,
1407; and also, in a preliminary study, the allylation reactivity
was observed to vary dramatically by the acidity of substratesꢀ
[23] a) V. Gevorgyan, K. Tando, N. Uchiyama, Y. Yamamoto, J. Org.
Chem. 1998, 63, 7022; b) H.-Y. Jang, R. R. Huddleston, M. J.
Krische, J. Am. Chem. Soc. 2004, 126, 4664.
[24] A similar pathway was previously proposed: H. Ito, K. Arimoto,
H. Sensul, A. Hosomi, Tetrahedron Lett. 1997, 38, 3977.
[25] CCDC 1434042 (3) and 1434043 (4k) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre.
À
C H bonds (see Figure S1 for details).
[14] One example of the Cu-catalyzed vinylation of polyfluoroarenes
with vinyl bromide was shown in the following report: H.-Q. Do,
O. Daugulis, J. Am. Chem. Soc. 2008, 130, 1128.
[15] a) D. J. Schipper, K. Fagnou, Chem. Mater. 2011, 23, 1594; b) Y.
Liu, X. Wan, F. Wang, J. Zhou, G. Long, J. Tian, Y. Chen, Adv.
Mater. 2011, 23, 5387; c) G. He, L. Kang, W. T. Delgado, O.
Received: November 2, 2015
Published online: December 23, 2015
1880
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