A general synthesis of fluoroalkylated alkenes by palladium-catalyzed Heck-type reaction of fluoroalkyl bromides

Article abstract of DOI:10.1002/anie.201409617

An efficient palladium-catalyzed Heck-type reaction of fluoroalkyl halides, including perfluoroalkyl bromides, trifluoromethyl iodides, and difluoroalkyl bromides, has been developed. The reaction proceeds under mild reaction conditions with high efficiency and broad substrate scope, and provides a general and straightforward access to fluoroalkylated alkenes which are of interest in life and material sciences.

Full text of DOI:10.1002/anie.201409617

Angewandte
Chemie
DOI: 10.1002/anie.201409617
Synthetic Methods
A General Synthesis of Fluoroalkylated Alkenes by Palladium-
Catalyzed Heck-Type Reaction of Fluoroalkyl Bromides**
Zhang Feng, Qiao-Qiao Min, Hai-Yang Zhao, Ji-Wei Gu, and Xingang Zhang*
Abstract: An efficient palladium-catalyzed Heck-type reaction
of fluoroalkyl halides, including perfluoroalkyl bromides,
trifluoromethyl iodides, and difluoroalkyl bromides, has been
developed. The reaction proceeds under mild reaction con-
ditions with high efficiency and broad substrate scope, and
provides a general and straightforward access to fluoroalky-
lated alkenes which are of interest in life and material sciences.
of this approach are its synthetic simplicity, broad substrate
scope, high efficiency, and excellent functional-group com-
patibility.
We began our study based on the fact that the addition of
the fluoroalkyl radical C to the alkenes 2 is kinetically
favorable compared with insertion of the palladium complex
[RfPdIILnX] (A) to 2 (Scheme 1).[6,7] Therefore, if C, instead of
A, is initiated by reaction of [Pd0Ln] with fluoroalkyl halides
T
he development of new methods to introduce fluorinated
functional groups into organic molecules has become an
intensive topic of synthetic organic chemistry because of the
importance of fluorinated compounds in agrochemicals,
pharmaceuticals, and functional materials.[1] To date, there
have been substantial efforts on fluoroalkylation of aromatic
compounds,[2] but alkenes containing fluorinated functional
groups are less studied owning to the lack of efficient and
general strategies. Usually, fluoroalkylated alkenes can be
prepared through cross-coupling of fluoroalkyl metal species
with alkenyl halides,[3] or stepwise procedures of addition of
fluoroalkyl free radical to alkenes, followed by base-assisted
elimination.[4] However, such processes suffer from the use of
stoichiometric amounts of a transition metal and/or the
requirement of multiple steps, in particular for preparation of
alkenyl halides and fluoroalkyl radical precursors. To circum-
vent these issues, transition-metal-catalyzed fluoroalkylation
of alkenes through Heck-type reactions appears to be an
appealing and straightforward alternative. Furthermore,
À
using low-cost and widely available fluoroalkyl halides (Rf
À
Scheme 1. Proposed mechanism for palladium-catalyzed fluoroalkyla-
tion of alkenes with fluoroalkyl halides.
X), in particular fluoroalkyl bromides (Rf Br), in the Heck-
type reactions would make the synthesis routine cost-efficient
for practical applications.[5] To date, however, the preparation
of fluoroalkylated alkenes through transition-metal-catalyzed
Heck-type reactions remains challenging. Herein, we disclose
the first example of a palladium-catalyzed Heck-type reaction
of perfluoroalkyl bromides. The reaction can also be extended
to trifluoromethyl iodide and other functionalized difluoro-
methyl bromides, thus providing a facile and general access to
a wide range of fluoroalkylated alkenes. The notable features
[7,8]
À
(1; Rf X),
then the recombination of the newly formed
alkyl radical D with [XPdILn] (B) would provide the key
palladium species [(alkyl)PdIILnX] (E; Scheme 1, Path A).[5]
As a consequence of b-hydride elimination of E, the desired
fluoroalkylated alkenes 3–5 would be delivered. To facilitate
the catalytic cycle, however, the competitive reactions
between the formation of E and the side product alkyl
halides 6 (Scheme 1, Path B) are a concern, because it has
been demonstrated by Chen et al. that among the fluoroalkyl
halides, perfluoroalkyl iodides, the most commonly used
radical precursors, are prone to yielding 6 in the presence of
a [Pd0Ln] catalyst.[7] In addition, other competitive side
reactions, such as oligomerization of 2 with D (Scheme 1,
Path C) and dimerization of D (Scheme 1, Path D), are also
hurdles to realizing such a Heck-type reaction. To the best of
our knowledge, no successful example of transition-metal-
catalyzed perfluoroalkylation of alkenes through Path A
(Scheme 1) has been reported thus far.[9]
[*] Z. Feng, Q.-Q. Min, H.-Y. Zhao, J.-W. Gu, Prof. Dr. X. Zhang
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
E-mail: xgzhang@mail.sioc.ac.cn
[**] This work was financially supported by the National Basic Research
Program of China (973 Program) (No. 2012CB821600 and
2015CB931900), the NSFC (21425208, 21421002, 21172242, and
21332010), and SIOC.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201409617.
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Accordingly, we chose perfluorohexyl bromide (1a) as
our initial substrate based on the following considerations:
(5 mol%), and K2CO3 (2.0 equiv) in 1,4-dioxane at 808C,
39% yield of 3a was obtained without observation of the by-
products 6–9 (entry 1). Switching the pre-palladium catalyst
from [PdCl2(PPh3)2] to [Pd(PPh3)4] dramatically improved the
yield to 62% (entry 2). Encouraged by these results, several
reaction parameters were investigated to improve the reac-
tion efficiency further (for details, see the Supporting
Information). It was found that 1,2-dichloroethane (DCE)
was the optimal solvent, and a higher yield (68%) was
obtained when the reaction was catalyzed by [PdCl2(PPh3)2]
in DCE (entry 3). Other palladium sources also catalyzed the
reaction, but led to lower yields (entries 4–8). The choice of
base also influenced the reaction efficiency, and the best yield
(89% upon isolation) was obtained with Cs2CO3 as a base
(entry 10). However, no reaction occurred when other
phosphine ligands other than Xantphos were used, thus
demonstrating the essential role of Xantphos in the catalytic
cycle (for details, see the Supporting Information). It should
be mentioned that the diminished yields were observed by
reducing the ratio of Pd/Xantphos from 1:2 to 1:1 (entries 11
and 12). In addition, neither the product nor by-products were
observed in the absence of the palladium sources or the base
(entries 13 and 14). Thus, these findings implied that the
tetraphosphine-ligated Pd0 species plays a crucial role in the
promotion of the reaction. Whereas no 3a was observed when
perfluorohexyl iodide (1a’) was tested under optimized
reaction conditions, a mixture of oligomerized by-products
(7a; Path C, Scheme 1), the dimer 9a (Path D), and other
uncertain by-products were provided as major products (for
details, see the Scheme S1 in the Supporting Information).
Furthermore, only a small amount of benzyl iodide derivative
6a (Path B) was observed in this reaction (for details, see the
Scheme S1 in the Supporting Information). We reasoned that
it is probably because of the high reactivity of Pd0/Xantphos
complex which may generate perfluoroalkyl radical from
perfluoroalkyl iodides faster than that from perfluoroalkyl
bromides, thus initiating different side reactions.
A variety of styrene derivatives could be fluoroalkylated
with 1a through this method (Table 2). Versatile functional
groups, such as alkoxycarbonyl and formyl were quite well-
tolerated (3h,i). In particular, the heterocyle thiazole fur-
nished the corresponding product in a synthetically useful
yield (3j). Branched alkenes were also applicable to the
reactions. Good yield was obtained, when cyclic alkene 1,2-
dihydronaphthalene (2k) was examined (3k). As for a termi-
nal branched alkene bearing an alkyl group, the double bond
migrated product was the only product obtained (3l), thus
providing an alternative strategy to access fluoroalkylated
allylic compounds. It is noteworthy that the conjugated alkene
underwent the reaction smoothly, thus providing 3m in good
yield without observation of other by-products. The alkenes
were not restricted to styrenes, as an enamide was also
a suitable substrate, thus providing perfluorohexylated alkene
with 81% yield (3o). In addition, the successful fluoroalky-
lation of dihydropyran makes it possible to rapidly access
fluorinated gylcomimetics for carbohydrate-based studies
(3n).[12] However, aliphatic alkenes were not suitable sub-
strates. Internal linear alkenes also failed to provide products
because of steric effects.
À
À
1) The C Br bond is stronger than the C I bond; as a result,
the generation of the side products 6–9 through Paths B–D
(Scheme 1) from perfluoroalkyl bromides would be slower
than that from perfluoroalkyl iodides. Although perfluor-
oalkyl bromides have been demonstrated to be poor fluo-
roalkyl radical precursors,[7] we envisioned that if a suitable
phosphine ligand in combination with a palladium catalyst
could induce perfluoroalkyl bromides to generate fluoroalkyl
radicals and accelerate Path A, it will benefit the formation of
desired products. 2) Perfluoroalkyl bromides are one of the
cheapest and most widely available fluorinated sources.
However, the transition-metal-catalyzed fluoroalkylation
reactions with perfluoroalkyl bromides remain underdevel-
oped, and represent a challenge because of their inert
reactivity. Therefore, it is of great interest to develop new
and efficient catalytic system for their wide applications in life
and materials sciences.
Initially, the coupling of 1a with styrene (2a) was
examined by using bidentate phosphine Xantphos as
a ligand which binds palladium with a large bite angle[10]
(Table 1). The use of Xantphos was inspired by our very
Table 1: Representative results for optimization of palladium-catalyzed
Heck-type reaction of 1a with styrene (2a).[a]
Entry
[Pd]
Solvent
Base
Yield [%][b]
1
2
3
4
5
6
7
8
[PdCl2(PPh3)2]
[Pd(PPh3)4]
[PdCl2(PPh3)2]
Pd(OAc)2
1,4-dioxane
1,4-dioxane
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
none
39
62
68
35
49
39
39
30
79 (81)
(89)
63
34
n.r.
n.r.
PdCl2
[PdCl2(dppf)]
[PdCl2(MeCN)2]
[Pd(PPh3)4]
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
none
9
10[c]
11[d]
12[e]
13
14
[PdCl2(PPh3)2]
DCE
[a] Reaction conditions (unless otherwise specified): 1a (0.6 mmol,
2.0 equiv), 2a (0.3 mmol, 1.0 equiv), solvent (2 mL), 24 h. [b] Deter-
mined by 19F NMR spectroscopy using fluorobenzene as an internal
standard and yield within parentheses is that of the isolated product.
[c] DCE (3 mL). [d] 7.5 mol% Xantphos was used. [e] 5 mol% Xantphos
was used. DCE=1,2-dichloroethane, dppf=1,1’-bis(diphenylphosphi-
no)ferrocene, n.r.=no reaction, Xantphos=9,9-dimethyl-4,5-bis(diphe-
nylphosphino)xanthene.
recent investigations into the palladium-catalyzed direct
difluoroalkylation of organoborons, in which a single-electron
transfer (SET) from a Pd0/Xantphos complex to difluoroalkyl
bromides initiated the catalytic cycle and gave difluoroalkyl
radicals.[11] To our delight, when the reaction was carried out
with Xantphos (10 mol%) in the presence of [PdCl2(PPh3)2]
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Table 2: Palladium-catalyzed Heck-type reaction of perfluorohexyl bro-
(4 f), thus providing good opportunities for downstream
mide with alkenes.[a]
transformations. Importantly, some styrene derivatives and
enamide were also suitable substrates for trifluoromethyl
iodide, thus leading to trifluoromethylated alkenes with high
efficiency (4g–l). However, it should be mentioned that the
reaction efficiency highly depends on the nature of the
substrates. Styrene gave a mixture of complexes, and only
a poor yield (16%) of trifluoromethylated alkene was
observed. para-Substituted styrenes, such as 1-methoxy-4-
vinylbenzene (2e) and methyl 4-vinylbenzoate (2h), also
afforded their corresponding products in low yields (2e, 31%;
2h, 15%) (for details, see the Scheme S2 in the Supporting
Information), along with the by-products 8 or 8’ (Path C,
Scheme 1) and 9 (Path D).[13]
The reaction can also be extended to bromodifluoroace-
tate (1h).[14] A series of difluoroacetylated alkenes were
obtained through this method with high efficiency and
excellent functional-group tolerance (Table 4). But in these
Table 4: Palladium-catalyzed Heck-type reaction of bromodifluoroace-
tate and its derivative with alkenes.[a]
[a] Reaction conditions (unless otherwise specified): 1a (0.6 mmol,
2.0 equiv), 2 (0.3 mmol, 1.0 equiv), DCE (3 mL), 24 h. All reported yields
are those of isolated products. [b] Reaction was conducted at 1208C.
To demonstrate the generality of this catalytic system,
other perfluoroalkyl bromides were also explored (Table 3).
Overall, perfluoroalkyl bromides containing seven to nine
carbon atoms all let to good yields (4a–d). In particular,
excellent yield (96%) was obtained when perfluoropropyl
bromide was tested (4e). 1,2-Dibromotetrafluoroethane was
also applicable to the reaction, and afforded the monoalke-
nylated product in moderate yield with one bromide intact
[a] Reaction conditions (unless otherwise specified): 1 (0.6 mmol,
2.0 equiv), 2 (0.3 mmol, 1.0 equiv), 1,4-dioxane (2 mL), 24 h. All reported
yields are those of isolated products. [b] Molecular sieves (3 ꢀ) were
used.
Table 3: Palladium-catalyzed Heck-type reaction of perfluoroalkyl bro-
mides and trifluoromethyl iodide with alkenes.[a]
cases, [PdCl2(MeCN)2] instead of [PdCl2(PPh3)4] showed
good activity. Interestingly, when indole derivative 2q was
subjected to the reaction, besides the desired product 5e,
a small amount of 5e’, with a second difluoroacetyl group
installed at C2, was also isolated (5e and 5e’). We supposed
that the formation of 5e’ was ascribed to the reaction of the
indole ring with free difluoroacetyl radical which was
generated by Pd/Xantphos/base with 1h. Most remarkably,
chromenone and quinolinone underwent the reactions
smoothly with the difluoroacetyl group exclusively intro-
duced at C3 position (5g and 5h). This reactivity is note-
worthy as chromenone and quinolinone are important scaf-
folds of natural products and display various biological
activities.[15] Therefore, this method is a valuable strategy for
chromenone and quinolinone modification and for the
discovery of new interesting molecules. Furthermore, the
phenylalanine derived bromodifluoroamide 1i also afforded
fluorinated alkene in good yield, thus providing a facile access
to complex fluorinated compounds (5i).
[a] Reaction conditions (unless otherwise specified): 1 (0.6 mmol,
2.0 equiv), 2 (0.3 mmol, 1.0 equiv), DCE (3 mL), 24 h. All reported yields
are those of isolated products. [b] [PdCl2(MeCN)2] (10 mol%), Xantphos
(20 mol%), K2CO3 (2 equiv), 1,4-dioxane (2 mL). [c] 4.0 equiv of CF3I was
used.
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Scheme 2. Synthesis of fluorinated biologically active compounds.
The importance of this protocol can also be featured by
the late-stage fluoroalkylation of bioactive molecules. As
shown in Scheme 2, treatment of the estrone-derived alkene
10 with 1a, 1g, and 1i afforded the corresponding fluoroalky-
lated alkenes 11–13 with high efficiency, thus providing
a facile access to diversified fluorinated bioactive molecules
from one key structure through present process.
To gain some mechanistic insight into the present
reaction, radical inhibition experiments were performed (for
details, see the Supporting Information). When a reaction
mixture of 1a and 2a was treated with the electron-transfer
scavenger 1,4-dinitrobenzene[16] or the radical inhibitor
hydroquinone in the presence of [PdCl2(PPh3)2] (5 mol%),
Xantphos (10 mol%), and Cs2CO3 in DCE, the yield of 3a
was significantly decreased, thus implying that a SET pathway
via a perfluorohexyl radical is involved in the catalytic cycle.
To further confirm that a free fluoroalkyl radical existed in
the reaction, a radical-clock experiment was conducted. As
illustrated in Scheme 3a, when compound 14, which is known
to participate in radical rearrangements,[17,18] was treated with
1a under the standard conditions, the compound 15 (65%
yield), instead of normal Heck-type product 16, was obtained.
This finding demonstrated that a perfluorohexyl free radical
was indeed generated in the reaction, because it has been
shown that if a free-radical species exists in the reaction, the
ring-opening products would be delivered with use of a-
cyclopropylstyrene.[18] What is more, this result also suggested
that the formation of the radical species G from F was faster
than the generation of key intermediate palladium complex I.
Additionally, to confirm that the fluoroalkylated alkenes were
not generated by a bromine-atom transfer radical addition to
an alkene (Path B, Scheme 1), followed by base-assisted
elimination of the resulting benzyl bromides, the reaction of
styrene with 1a in the presence of [Pd(PPh3)4] and Xantphos
without the base was conducted (Scheme 3b). We found that
the benzyl bromide 17 was not generated (detected by GC).
Instead, the perfluorohexylated alkene 3a was observed in
5% yield (determined by 19F NMR spectroscopy). This result
is in sharp contrast to the result illustrated in Table 1 entry 2,
because if Path B was feasible in the reaction, a high yield of
17 should be observed in the absence of base. Thus, the
formation of fluoroalkylated alkenes by the above-mentioned
Scheme 3. Experiments for mechanistic studies.
two-stepwise process (Path B) could be ruled out. This was
further confirmed by the following experiments. As shown in
Scheme 3c, when 17 was treated with Cs2CO3 at 808C, only
less than 5% yield of 3a was observed and 85% of 17 was
recovered. Furthermore, treatment of 17 in the presence of
[PdCl2(PPh3)2] and Xantphos under standard conditions led
to 3a in low yield (12%), along with some uncertain by-
products as major products (Scheme 3d). Thus, these results
demonstrated that the proposed mechanism (Path A) illus-
trated in Scheme 1 is reasonable.
In conclusion, we have demonstrated the first example of
palladium-catalyzed Heck-type fluoroalkylation of alkenes
with perfluoroalkyl bromides. The reaction can also be
extended to trifluoromethyl iodide, and other functionalized
difluoromethyl bromides. The method allows fluoroalkylation
of a variety of alkenes with high efficiency, in which the
bidentate ligand Xantphos is essential for the reaction. A
notable feature of this protocol is the late-stage fluoroalky-
lation of bioactive compounds in good yields, thus providing
an efficient and straightforward route for application in drug
discovery and development. Mechanistic studies reveal that
the free fluoroalkyl radicals initiated by a [Pd0/Xantphos]
complex through a SET pathway is involved in the Heck-type
catalytic cycle.
Received: September 30, 2014
Published online: && &&, &&&&
4
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[7] For a pioneering study of palladium-initiated fluoroalkyl radicals
Keywords: alkenes · fluoroalkylation · halides · palladium ·
synthetic methods
.
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T. F. Jamison, J. Am. Chem. Soc. 2013, 135, 1585; d) R.
Matsubara, A. C. Gutierrez, T. F. Jamison, J. Am. Chem. Soc.
2011, 133, 19020; e) K. S. Bloome, R. L. McMahen, E. J.
Alexanian, J. Am. Chem. Soc. 2011, 133, 20146; f) Y. Zou, J. S.
Zhou, Chem. Commun. 2014, 50, 3725.
[6] [RfPdI(PPh3)2] complexes are thermally stable and melted
between 250 and 3008C without decomposition. See: a) D. T.
Rosevear, F. G. A. Stone, J. Chem. Soc. A 1968, 164; b) H. D.
Empsall, M. Green, F. G. A. Stone, J. Chem. Soc. Dalton Trans.
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Soc. A 1969, 3203.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Synthetic Methods
Z. Feng, Q.-Q. Min, H.-Y. Zhao, J.-W. Gu,
X. Zhang*
&&&& — &&&&
A General Synthesis of Fluoroalkylated
Alkenes by Palladium-Catalyzed Heck-
Type Reaction of Fluoroalkyl Bromides
Simplicity is beauty: The title reaction
features a broad substrate scope and
excellent functional-group compatibility.
Mechanistic studies reveal that the free
fluoroalkyl radicals initiated by [Pd0Ln]
through a single-electron transfer path-
way is involved in the Heck-type catalytic
cycle.
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!