Ligand-Promoted Iron(III)-Catalyzed Hydrofluorination of Alkenes

Article abstract of DOI:10.1002/anie.201902607

An iron-catalyzed hydrofluorination of unactivated alkenes has been developed. The use of a multidentate ligand and the fluorination reagent N-fluorobenzenesulfonimide (NFSI) proved to be critical for this reaction, which afforded various fluorinated comp

Full text of DOI:10.1002/anie.201902607

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Title: Ligand-Promoted Fe(III)-Catalyzed Hydrofluorination of Alkenes
Authors: Mengchun Ye, yongtao xie, Peng-Wei Sun, Yuxin Li, Siwei
Wang, and Zhengming Li
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Ligand-Promoted Fe(III)-Catalyzed Hydrofluorination of Alkenes
Yongtao Xie, Peng-Wei Sun, Yuxin Li, Siwei Wang, Mengchun Ye*, Zhengming Li*
Dedicated to 100th anniversary of Nankai University
Abstract: An iron-catalyzed hydrofluorination of unactivated alkenes
has been developed. The use of multi-dentate ligand and fluorination
reagent (NFSI) proved to be critical for this reaction, affording
various fluorinated compounds in up to 94% yield.
hydrofluorination of alkenes, respectively, an iron-catalyzed
version still remains an elusive challenge. Herein we reported an
iron-catalyzed hydroflurination of unactivated alkene under non-
acidic conditions for the first time. The combination of multi-
dentate ligand, (EtO)3SiH and N-fluorobenzenesulfonimide
(NFSI) proves critical to facilitate the catalyzed reaction,
providing various substituted fluorinated compounds in up to 93%
yield (Scheme 1c).
Hydrofluorination of readily available unactivated alkenes has
become one of the most efficient methods for accessing to
fluorinated compounds that widely exist in pharmaceuticals,
agrochemicals and materials.[1,2] According to different
mechanistic process, hydrofluorination of alkenes can be divided
into two general types.[3] The first one relies on the use of proton
as hydrogen source. The proton reacts with an alkene to form a
hydroalkyl cation, which further combines a fluorine anion to
generate fluorinated products (Scheme 1a, path i). In this field,
the pioneering system (HF-pyridine) was developed by Olah and
co-workers, but it works for a pretty narrow range of functional-
free alkenes because the acidity of HF is relatively low.[4] When
a super-acid system (HF-SbF5) was introduced by Thibaudeau
and co-workers in 2007, the increased acidity led to significant
improvement of the reactivity and a series of substituted allylic
amines were well tolerated.[5] Recently, Xu and co-workers
designed a powerful bifunctional acid system (HF-KHSO4),
which significantly enhanced the reactivity and expanded the
scope of alkenes.[6] However, despite these great advance, the
requirement of strong acid in the reaction results into low
tolerance of acid-sensitive functional groups. And thus, the
development of a non-acidic reaction system is still desired.
In this context, the second type of hydrofluorination that uses
hydride as the hydrogen source received increasing attentions
(Scheme 1a, path ii). A metal-hydride species that comes from
the reaction of transition metals and reductants is inserted by an
alkene to afford an alkyl radical species, which was then trapped
by an electrophilic fluorination reagent to give final fluorinated
compounds. The breakthrough was achieved by Boger and co-
workers, who developed an iron-mediated hydrofluorination of
various unactivated alkenes by the use of NaBH4-Selectfluor
system (Scheme 1b).[7] Although stoichiometric amounts of iron
were needed in the reaction, some unique characteristics
including rapid reaction rate, high functional group tolerance and
the use of abundant and biocompatible iron metal render this
method attractive. To make this method more economical, much
effort has been devoted to reduce the amounts of iron. However,
despite big progress that has been made by Hiroya[8] and
Gouverneur group[9] in developing Co- and Pd-catalyzed
Scheme 1. Hydrofluorination of unactivated alkenes.
A general challenging problem in FeH-involved reactions is
the regeneration of Fe catalyst.[10] In 2014, Baran and co-worker
reported an elegant strategy for this problem. They introduced
an electron-withdrawing alkene to trap the alkyl radical that was
formed by insertion of the alkene into the Fe(III)H.[11] Then the
newly-formed radical bearing with
a proximate electron-
withdrawing group can easily oxidize the Fe(II) into the Fe(III).
This effective strategy has inspired many analogous successful
reaction designs.[12] We envisioned that a fluorination reagent
bearing with an electron-withdrawing group, for example, NFSI,
could also regenerate the iron because it will release an
electron-deficient benzenesulfonamide N radical to oxidize the
Fe(II).
Following this hypothesis, we selected 1,1-disubstituted
alkene 1a as the model substrate and NFSI as the fluorination
reagent to test the Boger’s hydrofluorination reaction. In the
beginning, various iron salts and H sources were screened, but
no reaction occurred. Gratifyingly, ligand examination revealed
that multi-dentate ligands had a big influence on the reactivity.
Through extensive investigation of various reaction parameters,
the optimal L6-complex with NaBH4 as H source was obtained to
facilitate the reaction smoothly (Scheme 2, the optimal
[*]
Y. Xie, P.-W. Sun, Y. Li, S. Wang, M. Ye, Z. Li
State Key Laboratory and Institute of Elemento-Organic Chemistry,
College of Chemistry, Nankai University, Tianjin 300071 (China)
E-mail: mcye@nankai.edu.cn, nkzml@vip.163.com
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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conditions A, entry 1). Control experiments showed that no
reaction occurred in the absence of iron catalyst or H source,
suggesting that both of them were requisite. The reaction is
pretty susceptible to iron and ligands (entries 210).
Tetradentate ligands bearing an ether-coordinating group
(L4L6), especially tetrahydrofuran group (L5)[13] and acetal
group (L6), displayed higher reactivity than other kinds of groups
such as alkyl (L1), alcohol (L2) and amine (L3) (entries 68 vs
35). Pre-formed complex of iron and ligand provided better
results than in-situ mixture of iron and the corresponding ligand
(entries 7, 8 and 10). In addition, the reaction was sensitive to H
source and fluorination reagents. Other boranes and F reagents
were completely ineffective in the reaction (entries 1116).
reaction occurred at room temperature. In addition, although
ligand structures still affected the yield (entries 2′10′), the
influence was smaller than that in NaBH4-mediated reactions.
For example, the absence of the ligand still delivered to the
desired product in 46% yield (entry 2′), and most of ligands
improved the reaction, providing 2a in 47% to 75% yield (entries
3′10′). The pre-formed L6-complex is still the optimal catalyst
(entry 1′ vs 8′). Similarly, the reaction was also highly susceptible
to silane and fluorination reagents (entries 11′16′). The
replacement of (EtO)3SiH or NFSI by other analogs resulted into
either lower yield or no reaction, suggesting that the combination
of NFSI and H source was critical to the reactivity of the iron
catalyst in the reaction.
Scheme 3. Scope of mono-substituted alkene. 1 (0.2 mmol) in EtOH (1.0 mL)
or EtOH:CH2Cl2 (1:2, 1.0 mL) at 75 C under N2 for 3 h, and isolated yield for
all products.
After establishing the optimal conditions, we first explored the
scope of mono-substituted alkenes (Scheme 3). Various alkyl
alkenes with different length of alkyl chains derived from alcohol
(2b to 2f) were well compatible with the current conditions,
providing the corresponding products in 8093% yield.
Functional groups such as bromo (2g), acetyl (2h) and
heteroaryls (2i and 2j) were also tolerated. The ester substrates
derived from acids instead of alcohols did not affect the reactivity
(2k and 2l). In addition, non-aryl-containing carboxylate groups
such as simple ester (2m) and amide (2n) also worked in the
reaction, leading to 64% and 72% yield, respectively. When the
alkyl chain was modified by introducing aryl group (2o) or
carbonyl (2p) did not have influence on the yield, providing the
Scheme 2. Reaction conditions deviation. 1a (0.2 mmol) in EtOH (2.0 mL for
conditions A; 1.0 mL for conditions B) under N2, and isolated yield for all
products. Ln-FeCl3: Ln (5 mol%) and FeCl3 (5 mol%).
To our surprise, when (EtO)3SiH was used to as H source, the
reaction can be greatly promoted by using the same iron catalyst
at elevated temperature (75 ºC) (the optimal conditions B,
entries 1′). However, different from the system of NaBH4, no
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corresponding product in 81% and 72% yield, respectively.
However, strong coordinating functional groups such as amino
and acid group were not compatible with the current reaction.
We reasoned that these strong coordinating groups could
strongly interact with the metal center, leading to complete
inactivation of the catalyst.
catalyst is sensitive to the substrate structure (3i to 3k). In
addition, various modifications on the alkyl chain such as all-
carbon chain (3q), aryl-containing chain (3r to 3t) and hydroxyl-
containing (3u and 3v) were all compatible with the current
reaction. Notably, alkyl acid-derived ester (3w) was still a good
substrate, providing 94% yield. In case of internal alkenes,
moderate yields were obtained, albeit with low selectivity (3x
and 3y). More sterically-hindered trisubstituted alkene was still
tolerated, but the yield significantly decreased to 42% (2a).
To further explore electronic and steric influence of substituted
groups adjacent to the alkene moiety, two competition
experiments were conducted. When equivalent moles of 1-
alkylalkene and styrene were mixed and subjected to the
standard conditions, only 1-alkylalkene provided the desired
product (Scheme 5, eq 1). Similarly, 1,1-disubstituted alkene
showed higher reactivity than 1,2-disubstituted alkene (eq 2).
These results showed that aryl group and steric hindrance was
unfavorable to the reaction.
Scheme 5. Competition experiments.
To further demonstrate the applicability of our method in
organic synthesis, some molecules bearing bioactive motifs
were tested (Scheme 6a). Dicamba-derived alkene produced the
corresponding fluorinated product in 71% yield (4a).[14] Likewise,
Probenecid- and Menbutone-derived alkene also worked well in
the current reaction, providing the desired products 4b and 4c in
72% and 82% yield, respectively.[15,16] The radical trapping
experiment by TEMPO obtained the corresponding product in 37%
yield, and intramolecular trapping reaction led to a mixture of cis
and trans cyclized products with a 1.6:1 ratio (Scheme 6b).
These results suggested that the process should be a radical
fluorination. Based on the previous FeH involved reactions [11,12]
and above-mentioned results, a plausible mechanism was
proposed for the current reaction. The insertion of alkene into
Fe(III)H species led to an Fe(II) and an alkyl radical.
Subsequently, the alkyl radical species was fluorinated by NFSI
to afford a benzenesulfonamide N radical that could be the key
oxidant to regenerate the Fe(III) (Scheme 6c).
Scheme 4. Scope of di- and trisubstituted alkene. 1 (0.2 mmol) in EtOH (1.0
mL) or EtOH:CH2Cl2 (1:2, 1.0 mL) at 75 C under N2 for 3 h, and isolated yield
for all products. [a] Ratio of trans:cis (trans isomer is major). [b] Ratio of
regioisomers. [c] Using trisubstituted alkene, 3-methylbut-2-en-1-yl 2-
naphthoate.
Next, various di- and trisubstituted alkenes were examined
(Scheme 4). Not like the acid-assisted hydrofluorination reaction,
di- and trisubstituted alkenes generally displayed relatively lower
reactivity than mono-substituted alkenes in transition metal-
catalyzed reactions because of steric hindrance. In the current
reaction, various 1,1-disubstituted alkenes bearing esters (3a
and 3b), ether (3c) and amide (3d) groups reacted very well to
provide the corresponding 3 alkyl fluorides in 6689% yield.
The esters bearing acid-sensitive TBS group (3e) and hydride-
sensitive OTs (3f) and formyl group (3p) were also well tolerated.
Commonly-used benzoates bearing various substituted groups
on the phenyl ring were also found to be suitable substrates (3g
to 3p). Notably, the position of the methoxy group on the phenyl
ring had a significant influence on the yield, suggesting the
In summary, we developed an iron-catalyzed hydrofluorination
of unactivated alkenes for the first time, providing a series of
alkyl fluorides in up to 93% yield. The combination of the
multidentate ligand, the fluorination reagent (NFSI) and the
hydride source ((EtO)3SiH) proved critical to the reactivity. This
ligand-promoted iron-catalyzed system could be potentially
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Scheme 6. Reaction utilization and proposed mechanism.
Acknowledgements
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We thank the National Key Research and Development Program
of China (2018YFD0200100 and 2017YFD0200505), and the
National Natural Science Foundation of China (21672107 and
21871145) for financial support.
Keywords: iron • alkene • hydrofluorination • silane • NFSI
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Yongtao Xie, Peng-Wei Sun, Yuxin Li,
Siwei Wang, Mengchun Ye*, Zhengming
Li*
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Ligand-Promoted Fe(III)-Catalyzed
Hydrofluorination of Alkenes
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